2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents

ABSTRACT

The present invention relates to new 2-Phenyl-1-[4-(2-Aminoethoxy)-Benzyl]-Indole compounds having the general structures below:  
                 
which are useful in treating uterine leiomyoma.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is continuation of U.S. Ser. No. 11/133,113, filed May19, 2005, which is a continuation application of U.S. Ser. No.10/916,118, filed Aug. 11, 2004, which is a continuation application ofU.S. Ser. No. 10/720,504 (now U.S. Pat. No. 6,835,729), filed Nov. 24,2003, which is a continuation application of U.S. Ser. No. 10/617,096(now U.S. Pat. No. 6,787,538), filed Jul. 10, 2003, which is acontinuation application of U.S. Ser. No. 10/192,069, filed Jul. 10,2002 (now abandoned), which is a continuation application of U.S. Ser.No. 09/974,416, filed Oct. 10, 2001 (now abandoned), which is adivisional application of U.S. Ser. No. 09/388,581, filed Sep. 2, 1999(now U.S. Pat. No. 6,326,367), which is a divisional application of U.S.Ser. No. 08/833,271 (now U.S. Pat. No. 5,998,402), filed Apr. 4, 1997,which claims the benefit of U.S. Application No. 60/015,553, filed Apr.19, 1996.

BACKGROUND OF THE INVENTION

The use of hormone replacement therapy for bone loss prevention inpost-menopausal women is well precedented. The normal protocol calls forestrogen supplementation using such formulations containing estrone,estriol, ethynyl estradiol or conjugated estrogens isolated from naturalsources (i.e. Premarin® conjugated estrogens from Wyeth-Ayerst). In somepatients, therapy may be contraindicated due to the proliferativeeffects of unopposed estrogens (estrogens not given in combination withprogestins) have on uterine tissue. This proliferation is associatedwith increased risk for endometriosis and/or endometrial cancer. Theeffects of unopposed estrogens on breast tissue is less clear, but is ofsome concern. The need for estrogens which can maintain the bone sparingeffect while minimizing the proliferative effects in the uterus andbreast is evident. Certain nonsteroidal antiestrogens have been shown tomaintain bone mass in the ovariectomized rat model as well as in humanclinical trials. Tamoxifen (sold as Novadex® brand tamoxifen citrate byZeneca Pharmaceuticals, Wilmington, Del.), for example, is a usefulpalliative for the treatment of breast cancer and has been demonstratedto exert an estrogen agonist-like effect on the bone, in humans.However, it is also a partial agonist in the uterus and this is causefor some concern. Raloxifene, a benzothiophene antiestrogen, has beenshown to stimulate uterine growth in the ovariectomized rat to a lesserextent than tamoxifen while maintaining the ability to spare bone. Asuitable review of tissue selective estrogens is seen in the article“Tissue-Selective Actions Of Estrogen Analogs”, Bone Vol. 17, No. 4,October 1995, 181S-190S.

The use of indoles as estrogen antagonists has been reported by VonAngerer, Chemical Abstracts, Vol. 99, No. 7 (1983), Abstract No. 53886u.Also, see, J. Med. Chem. 1990, 33, 2635-2640; J. Med. Chem. 1987, 30,131-136. Also see Ger. Offen., DE 3821148 A1 891228 and WO 96/03375.These prior art compounds share some structural similarities with thepresent compounds, but are functionally different. For compoundscontaining a basic amine, there is no phenyl group to rigidify the sidechain. The reported data for these compounds indicates that they mayhave a weaker binding to estrogen receptor than the compounds of thepresent invention and the reported compounds containing the basic sidechain show some uterotrophic effect in the rat uterus. One compound fromthe listed family of compounds in WO 96/03375 possesses a benzyl group,but does not have a basic side chain. The majority of these compoundsfall into a class of compounds best characterized as being “pureantiestrogens”. Many of the compounds described presently, due to theirparticular side chain, act as pure antiestrogens in the uterus, however,show strong estrogenic action in the bone and cardiovascular systems. Nosuch action is demonstrated for the related prior art compoundsdescribed herein.

WO A 95 17383 (Kar Bio AB) describes indole antiestrogens with longstraight chains. Another related patent WO A 93 10741 describes5-Hydroxyindole with a generic descriptor incorporating other sidechains. WO 93/23374 (Otsuka Pharmaceuticals, Japan) describes compoundswhich differ from the present invention; where R₃ in the presentformulas I and II, below, is defined as thioalkyl and the referencediscloses no such compounds having chains from the indole nitrogenhaving the same structure as the ones provided by the present invention.Where the side chain claimed is similar to that described herein, thecompounds are amides: Acylated indoles are not claimed in the presentinvention.

DESCRIPTION OF THE INVENTION

2-Phenylindoles of the general structure type shown in formulas (I) and(II) are estrogen agonists/antagonists useful for the treatment ofdiseases associated with estrogen deficiency. The compounds of thepresent invention show strong binding to the estrogen receptor. In vitroassays, including an Ishikawa alkaline phoshatase assay and an EREtransfection assay, show these compounds are antiestrogens with littleto no intrinsic estrogenicity and they have proven capable of completelyantagonizing the effects of 17β-estradiol while showing little or nouterine stimulation in a rat uterine assay when dosed alone.Additionally, some of these compounds are capable of inhibiting boneloss in an ovariectomized rat while showing little or no uterinestimulation. These compounds also decrease the weight gain normally seenin the ovariectomized animals as well as reduce total cholesterollevels.

The present invention includes compounds of the formulas I or II, below:

wherein:

R₁ is selected from H, OH or the C₁-C₁₂ esters (straight chain orbranched) or C₁-C₁₂ (straight chain or branched or cyclic) alkyl ethersthereof, or halogens; or C₁-C₄ halogenated ethers includingtrifluoromethyl ether and trichloromethyl ether.

R₂, R₃, R₄, R₅, and R₆ are independently selected from H, OH or theC₁-C₁₂ esters (straight chain or branched) or C₁-C₁₂ alkyl ethers(straight chain or branched or cyclic) thereof, halogens, or C₁-C₄halogenated ethers including trifluoromethyl ether and trichloromethylether, cyano, C₁-C₆ alkyl (straight chain or branched), ortrifluoromethyl, with the proviso that, when R₁ is H, R₂ is not OH.

X is selected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl,halogen;

n is 2 or 3;

Y is selected from:

-   -   a) the moiety:    -   wherein R₇ and R₈ are independently selected from the group of        H, C₁-C₆ alkyl, or phenyl optionally substituted by CN, C₁-C₆        alkyl (straight chain or branched), C₁-C₆ alkoxy (straight chain        or branched), halogen, —OH, —CF₃, or —OCF₃;    -   b) a five-membered saturated, unsaturated or partially        unsaturated heterocycle containing up to two heteroatoms        selected from the group consisting of —O—, —NH—, —N(C₁C₄        alkyl)-, —N═, and —S(O)_(m)—, wherein m is an integer of from        0-2, optionally substituted with 1-3 substituents independently        selected from the group consisting of hydrogen, hydroxyl, halo,        C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄        acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄        alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—,        —NH₂—, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R₁—,        —NHCOR₁—, —NO₂, and phenyl optionally substituted with 1-3        (C₁-C₄)alkyl;    -   c) a six-membered saturated, unsaturated or partially        unsaturated heterocycle containing up to two heteroatoms        selected from the group consisting of —O—, —NH—, —N(C₁C₄        alkyl)-, —N═, and —S(O)_(m)—, wherein m is an integer of from        0-2, optionally substituted with 1-3 substituents independently        selected from the group consisting of hydrogen, hydroxyl, halo,        C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄        acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄        alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—,        —NH₂—, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R₁—,        —NHCOR₁—, —NO₂, and phenyl optionally substituted with 1-3        (C₁-C₄)alkyl;    -   d) a seven-membered saturated, unsaturated or partially        unsaturated heterocycle containing up to two heteroatoms        selected from the group consisting of —O—, —NH—, —N(C₁C₄        alkyl)-, —N═, and —S(O)_(m)—, wherein m is an integer of from        0-2, optionally substituted with 1-3 substituents independently        selected from the group consisting of hydrogen, hydroxyl, halo,        C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄        acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄        alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—,        —NH₂—, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R₁—,        —NHCOR₁—, —NO₂, and phenyl optionally substituted with 1-3        (C₁-C₄)alkyl; or    -   e) a bicyclic heterocycle containing from 6-12 carbon atoms        either bridged or fused and containing up to two heteroatoms        selected from the group consisting of —O—, —NH—, —N(C₁C₄        alkyl)-, and —S(O)_(m)—, wherein m is an integer of from 0-2,        optionally substituted with 1-3 substituents independently        selected from the group consisting of hydrogen, hydroxyl, halo,        C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄        acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄        alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—,        —NH₂—, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R₁—,        —NHCOR₁—, —NO₂, and phenyl optionally substituted with 1-3        (C₁-C₄) alkyl; and the pharmaceutically acceptable salts        thereof.

The more preferred compounds of this invention are those having thegeneral structures I or II, above, wherein:

R₁ is selected from H, OH or the C₁-C₁₂ esters or alkyl ethers thereof,halogen;

R₂, R₃, R₄, R₅, and R₆ are independently selected from H, OH or theC₁-C₁₂ esters or alkyl ethers thereof, halogen, cyano, C₁-C₆ alkyl, ortrihalomethyl, preferably trifluoromethyl, with the proviso that, whenR₁ is H, R₂ is not OH;

X is selected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl,halogen;

Y is the moiety

R₇ and R₈ are selected independently from H, C₁-C₆ alkyl, or combined by—(CH₂)p—, wherein p is an integer of from 2 to 6, so as to form a ring,the ring being optionally substituted by up to three substituentsselected from the group of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN,—CONH(C₁-C₄), —NH₃, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, —NHSO₂(C₁-C₄),—NHCO(C₁-C₄), and —NO₃; and the pharmaceutically acceptable saltsthereof.

The rings formed by a concatenated R₇ and R₈, mentioned above, mayinclude, but are not limited to, aziridine, azetidine, pyrrolidine,piperidine, hexamethyleneamine or heptamethyleneamine rings.

The most preferred compounds of the present invention are those havingthe structrual formulas I or II, above, wherein R₁ is OH; R₂-R₆ are asdefined above; X is selected from the group of Cl, NO₂, CN, CF₃, or CH₃;and Y is the moiety

and R₇ and R₈ are concatenated together as —(CH₂)_(r)—, wherein r is aninteger of from 4 to 6, to form a ring optionally substituted by up tothree subsituents selected from the group of hydrogen, hydroxyl, halo,C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄)alkyl, —NH₂, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄)alkyl, —NHCO(C₁-C₄)alkyl, and —NO₂;and the pharmaceutically acceptable salts thereof.

In another embodiment of this invention, when R₇ and R₈ are concatenatedtogether as —(CH₂)p—, wherein p is an integer of from 2 to 6, preferably4 to 6, the ring so formed is optionally substituted with 1-3substituents selected from a group containing C₁-C₃ alkyl,trifluoromethyl, halogen, hydrogen, phenyl, nitro, —CN.

The invention includes sulfate, sulfamates and sulfate esters ofphenolic groups. Sulfates can be readily prepared by the reaction of thefree phenolic compounds with sulfur trioxide complexed with an aminesuch as pyridine, trimethylamine, triethylamine, etc. Sulfamates can beprepared by treating the free phenolic compound with the desired aminoor alkylamino or dialkylamino sulfamyl chloride in the presence of asuitable base such as pyridine. Sulfate esters can be prepared byreaction of the free phenol with the desired alkanesulfonyl chloride inthe presence of a suitable base such as pyridine. Additionally, thisinvention includes compounds containing phosphates at the phenol as wellas dialkyl phoshates. Phosphates can be prepared by reaction of thephenol with the appropriate chlorophosphate. The dialkylphosphates canbe hydrolyzed to yield the free phosphates. Phosphinates are alsoclaimed where the phenol is reacted with the desired dialkylphosphinicchloride to yield the desired dialkylphosphinate of the phenol.

The invention includes acceptable salt forms formed from the additionreaction with either inorganic or organic acids. Inorganic acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,phoshoric acid, nitric acid useful as well as organic acids such asacetic acid, propionic acid, citric acid, maleic acid, malic acid,tartaric acid, phthalic acid, succinic acid, methanesulfonic acid,toluenesulfonic acid, napthalenesulfonic acid, camphorsulfonic acid,benzenesulfonic acid are useful. It is known that compounds possessing abasic nitrogen can be complexed with many different acids (both proticand non-protic) and usually it is preferred to administer a compound ofthis invention in the form of an acid addition salt. Additionally, thisinvention includes quaternary ammonium salts of the compounds herein.These can be prepared by reacting the nucleophilic amines of the sidechain with a suitably reactive alkylating agent such as an alkyl halideor benzyl halide.

Methods

Compounds of this invention can be synthesized in a general senseaccording to Scheme 1, below.

The initial indole synthesis is accomplished by heating an appropriatelysubstituted alpha-bromo ketone (b) with the desired aniline (a) in DMFto form the indole (c). The product is then alkylated with a benzylchloride (e) to give the substituted indole (f). The benzyl chloride (e)can be readily prepared from the aldehyde (d) in 2 steps as given.Product (g) can be prepared from (f) by reduction of the ester,conversion of the alcohol to a bromide, displacement of the bromide withthe desired amine in a suitable solvent such as THF or DMF, and finally,deprotection if necessary. Deprotection is necessary when either R₁ orR₂ or both is a protected phenol. The preferred protecting group is abenzyl group which can be conveniently removed by several conventionalmethods, especially hydrogenolysis.

For the synthesis of compounds with X=H, halogen, trifluoromethyl,cyano, nitro, an alternative synthesis shown in scheme 2 may bepreferable. The formation of halogens at the 3-position can be easilyperformed with such reagents as N-chlorosuccinamide, N-bromosuccinamide,or N-iodosuccinamide. A 3-Iodoindole compound obtained can be used as aprecursor to the 3-trifluoromethyl compound by a coupling reactionutilizing a palladium catalyst and bistrifluoromethyl mercury (II). Acompound with a cyano group in the 3-position can be prepared byelectrophilic cyanation or alternatively the 3-position can beformylated (with a formyl iminium salt, for example) then the formylgroup converted to an oxime and subsequently dehydrated to a nitrile.Alternatively, the 3-cyano compound can be synthesized by reaction ofthe 3-unsubstituted indole with chlorosulfonylisocyanate followed bytriethylamine. A compound with the nitro group in the 3-position can beprepared by treating the indole with sodium nitrite and acetic acid. Oneskilled in the art recognizes these routes are not limiting and otherroutes are also available.

Synthesis of selected representative examples are given in the followingschemes:

The synthesis of analogues with a 3-carbon chain (example No. 166)between the oxygen and the basic amine can be accomplished as shown inscheme 4.

The synthetic procedure shown in scheme 4 may be used for compounds withtwo carbon chains analogous to example No. 97 in scheme 3. This is shownin scheme 4a for the synthesis of example No. 127.

The synthesis of indoles with alternative substituents (CN, Cl) at the3-position of the indole both utilize the 3-unsubstituted indole No. 141for a precursor. The indole is synthesized by the Fisher methodutilizing the hydrazone derived from the condensation of4-benzyloxyacetophenone CAS No. [54696-05-8] and4-benzyloxyphenylhydrazine CAS No. [51145-58-5]. The hydrazone No. 140is then cyclized in acetic acid using zinc chloride to afford thedesired indole No. 141. This synthesis can be seen in scheme 5.

The synthesis of 3-Chloroindole compounds is demonstrated for exampleNo. 134 and shown, infra, in scheme 6. The indole No. 141 from scheme 5is chlorinated with N-chlorosuccinamide. The 3-Chloroindole No. 142,thus obtained, is taken to the final product in analogous fashion tothat shown in scheme 3.

3-Cyano analogues are synthesized from the precursor indole No. 141 asshown in Scheme 7. Reaction of the precursor indole No. 141 withchlorosulfonyl isocyanate followed by addition of triethylamine yieldsthe 3-Cyanoindole No. 155. The side chain is made by conversion of thebenzylic alcohol of CAS No. [111728-87-1] to the benzylic bromide No.156 using thionyl bromide in THF. The indole is alkylated by the sidechain in DMF using sodium hydride to give the intermediate No. 157. Thiscan then be taken to the final product No. 138 in an analogous fashionto that shown in scheme 4.

The compounds of the invention are selective estrogen agonists anddisplay high affinity for the estrogen receptor. Unlike many estrogens,however, many of these compounds do not cause increases in uterine wetweight. These compounds are antiestrogenic in the uterus and cancompletely antagonize the trophic effects of estrogen agonists inuterine tissue. Due to the tissue selective nature of these compounds,they are useful in treating or preventing in a mammal disease states orsyndromes which are caused or associated with an estrogen deficiency (incertain tissues such as bone or cardiovascular) or an excess of estrogen(in the uterus or mammary glands). They may also be used in methods oftreatment for diseases or disorders which result from proliferation orabnormal development, actions or growth of endometrial orendometrial-like tissues.

The present compounds have the ability to behave like estrogen agonistsby lowering cholesterol and preventing bone loss. These compounds areuseful for treating many maladies which result from estrogen effects andestrogen excess or deficiency including osteoporosis, prostatichypertrophy, male pattern baldness, vaginal and skin atrophy, acne,dysfunctional uterine bleeding, endometrial polyps, benign breastdisease, uterine leiomyomas, adenomyosis, ovarian cancer, infertility,breast cancer, endometriosis, endometrial cancer, polycystic ovarysyndrome, cardiovascular disease, contraception, Alzheimer's disease,cognitive decline and other CNS disorders, as well as certain cancersincluding melanoma, prostrate cancer, cancers of the colon, CNS cancers,among others. Additionally, these compounds can be used forcontraception in pre-menopausal women, as well as hormone replacementtherapy in post-menopausal women or in other estrogen deficiency stateswhere estrogen supplementation would be beneficial. They may also beused in disease states where amenorrhea is advantageous, such asleukemia, endometrial ablations, chronic renal or hepatic disease orcoagulation diseases or disorders.

The compounds of this invention may also be used in methods of treatmentfor and prevention of bone loss, which may result from an imbalance inan individual's formation of new bone tissues and the resorption ofolder tissues, leading to a net loss of bone. Such bone depletionresults in a range of individuals, particularly in post-menopausalwomen, women who have undergone bilateral oophorectomy, those receivingor who have received extended corticosteroid therapies, thoseexperiencing gonadal dysgenesis, and those suffering from Cushing'ssyndrome. Special needs for bone, including teeth and oral bone,replacement can also be addressed using these compounds in individualswith bone fractures, defective bone structures, and those receivingbone-related surgeries and/or the implantation of prosthesis. Inaddition to those problems described above, these compounds can be usedin treatments for osteoarthritis, hypocalcemia, hypercalcemia, Paget'sdisease, osteomalacia, osteohalisteresis, multiple myeloma and otherforms of cancer having deleterious effects on bone tissues. Methods oftreating the maladies listed herein are understood to compriseadministering to an individual in need of such treatment apharmaceutically effective amount of one or more of the compounds ofthis invention or a pharmaceutically acceptable salt thereof. Thisinvention also includes pharmaceutical compositions utilizing one ormore of the present compounds, and/or the pharmaceutically acceptablesalts thereof, along with one or more pharmaceutically acceptablecarriers, excipients, etc.

It is understood that the dosage, regimen and mode of administration ofthese compounds will vary according to the malady and the individualbeing treated and will be subject to the judgement of the medicalpractitioner involved. It is preferred that the administration of one ormore of the compounds herein begin at a low dose and be increased untilthe desired effects are achieved.

Effective administration of these compounds may be given at a dose offrom about 0.1 mg/day to about 1,000 mg/day. Preferably, administrationwill be from about 10 mg/day to about 600 mg/day, more preferably fromabout 50 mg/day to about 600 mg/day, in a single dose or in two or moredivided doses. Such doses may be administered in any manner useful indirecting the active compounds herein to the recipient's bloodstream,including orally, via implants, parenterally (including intravenous,intraperitoneal and subcutaneous injections), rectally, vaginally, andtransdermally. For the purposes of this disclosure, transdermaladministrations are understood to include all administrations across thesurface of the body and the inner linings of bodily passages includingepithelial and mucosal tissues. Such administrations may be carried outusing the present compounds, or pharmaceutically acceptable saltsthereof, in lotions, creams, foams, patches, suspensions, solutions, andsuppositories (rectal and vaginal).

Oral formulations containing the active compounds of this invention maycomprise any conventionally used oral forms, including tablets,capsules, buccal forms, troches, lozenges and oral liquids, suspensionsor solutions. Capsules may contain mixtures of the active compound(s)with inert fillers and/or diluents such as the pharmaceuticallyacceptable starches (e.g. corn, potato or tapioca starch), sugars,artificial sweetening agents, powdered celluloses, such as crystallineand microcrystalline celluloses, flours, gelatins, gums, etc. Usefultablet formulations may be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants,suspending or stabilizing agents, including, but not limited to,magnesium stearate, stearic acid, talc, sodium lauryl sulfate,microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations herein may utilize standard delay or timerelease formulations to alter the absorption of the active compound(s).Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

Aldrich Sure Seal™ Solvents, anhydrous without further purification, maybe used for the reactions described herein and may be obtained fromAldrich Chemical Company. All reactions were carried out under anitrogen atmosphere. Chromatography was performed using 230-400 meshsilica gel (Merck Grade 60, Aldrich Chemical Company). Thin layerchromatography was performed with Silica Gel 60 F₂₅₄ plates from EMScience. ¹H NMR spectra were obtained on a Bruker AM-400 or BrukerDPX-300 instrument in DMSO and chemical shifts reported in ppm. Meltingpoints were determined on a Thomas-Hoover apparatus and are uncorrected.IR spectra were recorded on a Perkin-Elmer diffraction grating orPerkin-Elmer 784 spectrophotometers. Mass spectra were recorded on aKratos MS 50 or Finnigan 8230 mass spectrometers. Elemental analyseswere obtained with a Perkin-Elmer 2400 elemental analyzer. Compounds forwhich CHN are reported are within 0.4% of the theoretical value for theformula given unless expressed otherwise. Compound nomenclature wasgenerally arrived at by use of the Beilstein Autonom™ program.

Synthesis of α-Bromo Ketones Method a

The synthesis of the alpha bromo ketones is conveniently accomplished bysimply dissolving the starting phenyl ketone in ethyl ether (0.05-0.10M) and at room temperature, 1.1 equivalents of bromine is added indropwise. The reaction can be monitored by TLC for consumption ofstarting materials. The reaction is worked up by washing with an aqueoussodium bicarbonate solution followed by a 10% aqueous sodium sulfitesolution. The ether layer is washed with brine and dried over magnesiumsulfate. Concentration of the reaction mixture typically yields thebromoketones in good yield and purity. The bromoketones were taken “asis” (without purification or characterization) to the next step.

3-Methyl Indoles

TABLE 1

Example No. X Q No. 1 H H No. 1a F OBn No. 2 H 4′-OBn No. 3 OBn H No. 4OBn 4′-OMe No. 5 OMe 4′-OMe No. 6 OBn 4′-OEt No. 7 OBn 4′-OBn No. 8 OBn4′-F No. 9 OBn 3′-OMe, 4′-OBn No. 10 OBn 3′,4′-OCH₂O— No. 11 OBn4′-O-iPr No. 12 OBn 4′-O-Cp No. 13 OBn 4′-CF₃ No. 14 OBn 4′-CH₃ No. 15OBn 4′-Cl No. 16 OBn 2′-OMe, 4′-OMe No. 17 OBn 3′-OBn No. 18 OBn 4′-OBn,3′-F No. 19 OBn 3′-OMe No. 20 OBn 4′-OCF₃

Method 1 Illustrated for Example No. 75-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole

A flask was charged with 4-benzyloxyaniline hydrochloride CAS No.[51145-58-5]. (45 g, 0.23 mol), 4′-benzyloxy-2-bromophenylpropiophenoneCAS No. [66414-19-5] (21 g, 0.066 mol), and 50 mL DMF. The reaction washeated at reflux for 30 minutes and then cooled to rt and thenpartitioned between 250 mL EtOAc and 100 mL 1N HCl (aq). The EtOAc waswashed with NaHCO₃ (aq) and brine, then dried over MgSO₄. The solutionwas concentrated and the residue taken up in CH₂Cl₂ and hexanes added toprecipitate out 25 g of a crude solid. The solid was dissolved in CH₂Cl₂and evaporated onto silica gel and chromatographed using CH₂Cl₂/Hexane(1:5) to yield 9.2 g of a tan solid (33%): Mp=150-152° C.; ¹H NMR (DMSO)10.88 (s, 1H), 7.56 (d, 2H, J=8.8 Hz), 7.48 (d, 4H, J=7.9 Hz), 7.42-7.29(m, 6H), 7.21 (d, 1H, J=7.0 Hz), 7.13 (d, 2H, J=8.8 Hz), 7.08 (d, 1H,J=2.2 Hz), 6.94 (dd, 1H, J=8.8, 2.4 Hz), 5.16 (s, 2H), 5.11 (s, 2H),2.33 (s, 3H); IR (KBr) 3470, 2880, 2820, 1620 cm⁻¹; MS eI m/z 419.

Method 2 (Shown in Scheme 8) Also Illustrated for Example No. 7

Reagents used were same as in method 1 except the additional use oftriethylamine in this method. The bromoketone CAS No. [66414-19-5] (50.0g, 0.16 mol) in 200 mL DMF was treated with the aniline hydrochlorideCAS No. [51145-58-5] (44 g, 0.22 mol) and the reaction purged withnitrogen for about 10 minutes. The triethylamine (54.6 mL) was added andthe reaction was heated at 120° C. for 2 hours. TLC analysis(EtOAc/hexanes) shows the starting material has dissappeared forming amore polar spot. The reaction mixture is allowed to cool down and anadditional 48 g of the aniline hydrochloride was added. The reaction washeated to 150° C. for 2 hours. An additional 5 grams of the anilinehydrochloride was added and the reaction was heated at 150° C. for anadditional 30 minutes. The reaction mixture is allowed to cool to roomtemperature and then poured into approximately 1.5 liters of water andextracted with 2 liters of ethyl acetate. Solids are dissolved withadditional ethyl acetate as necessary. The ethyl acetate layer is washedwith 1 liter of 1 N NaOH solution aq., 1 liter of water, brine, thendried over magnesium sulfate and filtered. The organic layers wereconcentrated down to yield a crude solid which is stirred with 500 mL ofmethanol and filtered. This solid is then stirred with 500 mL of ethylether and filtered. The solid is stirred alternatively with methanol andether until it is of whitish color and has a melting point similar tothat described for No. 7 in method 1. Reaction yields 36 grams ofproduct.

Physical Data for Indoles

The following 3-methyl indoles (No. 1-No. 20) were synthesized accordingto the procedure outlined in scheme 2 using method 2 using theappropriately substituted bromoketones (prepared as given above) andanilines (commercially available; Aldrich) as starting materials.

EXAMPLE NO. 1 2-Phenyl-3-methyl-1H-indole

Mp=90-94° C.; ¹H NMR (DMSO) 11.13 (s, 1H), 7.68-7.64 (m, 2H), 7.54-7.46(m, 3H), 7.37-7.32 (m, 2H), 7.12-7.06 (m, 1H), 7.03-6.97 (m, 1H), 2.40(s, 3H); MS eI m/z 207 (M+).

EXAMPLE NO. 1a 5-Flouro-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole

Mp=143-146° C.

EXAMPLE NO. 2 2-(4-Benzyloxy-phenyl)-3-methyl-1H-indole

Mp=118-120° C.; ¹H NMR (DMSO) 11.03 (s, 1H), 7.57 (dd, 2H, J=2.0 Hz, 6.6Hz), 7.48-7.46 (m, 3H), 7.44-7.28 (m, 4H), 7.18-7.11 (m, 2H), 7.08-7.03(m, 1H), 7.0-6.95 (m, 1H), 5.16 (s, 2H), 2.36 (s, 3H); MS eI m/z 313(M+).

EXAMPLE NO. 3 5-Benzyloxy-2-phenyl-3-methyl-1H-indole

Mp=141-144° C.; ¹H NMR(DMSO) 10.98 (s, 1H), 7.65-7.61 (m, 2H), 7.51-7.44(m, 4H), 7.42-7.28 (m, 4H), 7.23 (d, 1H, J=8.8 Hz), 7.10 (d, 1H, J=2.5Hz), 6.80 (d, 1H, J=6.0 Hz), 5.10 (s, 2H), 2.36 (s, 3H); MS eI m/z 313(M+).

EXAMPLE NO. 4 5-Benzyloxy-2-(4-methoxy-phenyl)-3-methyl-1H-indole

Mp=158° C.; ¹H NMR 10.85 (brs, 1H), 7.56 (d, 2H, J=8.8 Hz), 7.48 (d, 2H,J=8.3 Hz), 7.45-7.36 (m, 2H), 7.34-7.28 (m, 1H), 7.21 (d, 1H, J=8.6 Hz),7.09-7.04 (m, 3H), 6.79 (dd, 1H, J=8.8 Hz), 5.11 (s, 2H), 3.80 (s, 3H),2.33 (s, 3H); IR (KBr) 3400, 2900, 1610 cm⁻¹; MS eI m/z 343 (M+); CHNcalcd for C₂₃H₂₁NO₂+0.25H₂O.

EXAMPLE NO. 5 5-methoxy-2-(4-methoxy-phenyl)-3-methyl-1H-indole

Mp=139-142° C.; ¹H NMR (DMSO) 10.85 (s, 1H), 7.57 (d, 2H, J=8.8 Hz),7.19 (d, 1H, J=8.6 Hz), 7.04 (d, 2H, J=6.8 Hz), 6.95 (d, 1H, J=2.2 Hz),6.71 (dd, 1H, J=8.5 Hz, J=2.4 Hz), 3.80 (s, 3H), 3.76 (s, 3H), 2.33 (s,3H); MS eI m/z 267 (M+); CHN calc for C₁₇H₁₇NO₂.

EXAMPLE NO. 6 5-Benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-1H-indole

Mp=143-145° C.; ¹H NMR (DMSO) 10.86 (s, 1H), 7.54 (d, 2H, J=8.5 Hz),7.46 (d, 2H, J=7.3 Hz), 7.41-7.37 (m, 2H), 7.32-7.30 (m, 1H), 7.20 (d,1H, J=8.6 Hz), 7.05 (d, 1H), 7.03 (d, 2H, J=8.8 Hz), 6.79 (dd, 1H, J=8.6Hz, J=2.4 Hz), 5.10 (s, 2H), 4.07 (q, 2H, J=6.8 Hz), 2.32 (s, 3H), 1.34(t, 3H, J=7.0 Hz); MS eI m/z 357 (M+).

EXAMPLE NO. 8 5-Benzyloxy-2-(4-fluoro-phenyl)-3-methyl)-1H-indole

Mp=132° C.; ¹H NMR (DMSO) 11.0 (s, 1H), 7.68-7.64 (m, 2H), 7.49-7.47 (m,2H), 7.41-7.31 (m, 5H), 7.23 (d, 1H, J=8.8 Hz), 7.10 (d, 1H, J=2.4 Hz),6.82 (dd, 1H, J=8.8, 2.4 Hz), 5.11 (s, 2H), 2.34 (s, 3H); MS EI m/z 331;CHN calcd for C₂₂H₁₈FNO.

EXAMPLE NO. 95-Benzyloxy-2-(4-benzyloxy-3-methoxy-phenyl)-3-methyl-1H-indole

Mp=155-158° C.; ¹H NMR (DMSO) 10.88 (s, 1H), 7.50-7.45 (m, 4H),7.41-7.35 (m, 6H), 7.22-7.20 (m, 2H), 7.14 (s, 2H), 7.08 (d, 1H, J=2.2Hz), 6.78 (dd, 1H, J=8.5 Hz, J=2.4 Hz), 5.13 (s, 2H), 5.11(s, 2H), 3.85(s, 3H), 2.35 (s, 3H); MS eI m/z 449 (M+).

EXAMPLE NO. 10 2-Benzo[1,3]dioxol-5-yl-5-benzyloxy-3-methyl-1H-indole

Mp=142-145° C.; ¹H NMR (DMSO) 10.86 (s, 1H), 7.48 (d, 2H, J=7.0 Hz),7.40-7.30 (m, 3H), 7.20 (m, 2H), 7.10-7.05 (m, 3H), 6.78 (dd, 1H, J=8.8Hz, J=2.4 Hz), 6.06 (s, 2H), 5.10 (s, 2H), 2.31 (s, 3H); MS eI m/z 357(M+); CHN calc for C₂₃H₁₉NO₃.

EXAMPLE NO. 11 5-Benzyloxy-2-(4-isopropoxy-phenyl)-3-methyl)-1H-indole

Mp=136-138° C.; ¹H NMR (DMSO) 10.86 (s, 1H), 7.55-7.51 (m, 2H),7.50-7.47 (d, 2H, J=7.3 Hz), 7.40-7.34 (m, 2H), 7.39-7.28 (m, 1H), 7.20(d, 1H, J=8.7 Hz), 7.06 (d, 1H, J=2.2 Hz), 7.02 (d, 2H, J=8.8 Hz), 6.77(dd, 1H, J=2.4 Hz, 8.8 Hz), 5.10 (s, 2H), 4.68-4.62 (m, 1H), 2.32 (s,3H), 1.28 (d, 6H, J=6.0 Hz); MS eI m/z 371 (M+).

EXAMPLE NO. 12 5-Benzyloxy-2-(4-cyclopenyloxy-phenyl)-3-methyl-1H-indole

Mp=161-167° C.; ¹H NMR (DMSO) 10.85 (s, 1H), 7.53 (d, 2H, J=8.8 Hz),7.47 (d, 2H, J=8.4 Hz), 7.40-7.36 (m, 2H), 7.33-7.28 (m, 1H), 7.20 (d,1H, J=8.6 Hz), 7.07 (d, 1H, J=2.4 Hz), 7.01 (d, 2H, J=8.8 Hz), 6.78 (dd,1H, J=8.6 Hz, 2.2 Hz), 5.10 (s, 2H), 4.88-4.84 (m, 1H), 2.32 (s, 3H),1.99-1.88 (m, 2H), 1.78-1.69 (m, 4H), 1.64-1.52 (m, 2H); IR (KBr) 3400,2920, 1600 cm⁻¹; MS eI m/z 397 (M+); CHN calcd for C₂₇H₂₇NO₂+0.25H₂O.

EXAMPLE NO. 135-Benzyloxy-2-(4-trifluoromethyl-phenyl)-3-methyl-1H-indole

¹H NMR (DMSO) 11.0 (br s, 1H), 7.87-7.82 (m, 4H), 7.48 (d, 2H, J=8.8Hz), 7.44-7.35 (m, 2H), 7.34-7.26 (m, 2H), 7.15 (d, 1H, J=2.2 Hz), 6.87(dd, 1H, J=8.6 Hz, 2.4 Hz), 5.12 (s, 2H), 2.41 (s, 3H); CHN calcd forC₂₃H₁₈F₃NO.

EXAMPLE NO. 14 5-Benzyloxy-2-(4-methyl-phenyl)-3-methyl-1H-indole

Mp=144-146° C.; ¹H NMR (DMSO) 10.91 (s, 1H), 7.56-7.20 (m, 10H), 7.08(d, 1H, J=2.4 Hz), 6.80 (dd, 1H, J=2.4 Hz, 8.6 Hz), 5.11 (s, 2H), 2.34(s, 3H), 2.34 (s, 3H); MS eI m/z 327(M+).

EXAMPLE NO. 15 5-Benzyloxy-2-(4-chloro-phenyl)-3-methyl-1H-indole

Mp=134-136° C.; ¹H NMR (DMSO) 11.04 (s, 1H), 7.65 (d, 2H, J=8.3 Hz),7.53 (d, 2H, J=8.5 Hz), 7.47 (d, 2H, J=6.8 Hz), 7.41-7.37 (m, 2H),7.31-7.28 (m, 1H), 7.25 (d, 1H, J=8.5 Hz), 7.11 (d, 1H, J=2.4 Hz), 6.82(dd, 1H, J=8.8 Hz, J=2.4 Hz), 5.11 (s, 2H), 2.35 (s, 3H); IR (KBr) 3380,1210 cm⁻¹, Ms eI m/z 347 (M+); CHN calc for C₂₂H₁₈ClNO₂.

EXAMPLE NO. 16 5-Benzyloxy-2-(2,4-dimethoxy-phenyl)-3-methyl-1H-indole

Oil; ¹H NMR (DMSO) 10.58 (s, 1H), 7.50-7.18 (m, 7H), 7.04 (d, 1H, J=2.4Hz), 6.76 (dd, 1H, J=2.3 Hz, 8.6 Hz), 6.69-6.62 (m, 2H), 5.11 (s, 2H),3.82 (s, 3H), 3.78 (s, 3H), 2.12 (s, 3H).

EXAMPLE NO. 17 5-Benzyloxy-2-(3-benzyloxy-phenyl)-3-methyl-1H-indole

Mp=83-86° C.

EXAMPLE NO. 185-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1H-indole

Mp=135-137° C.; ¹H NMR (DMSO) 10.94 (s, 1H), 7.50-7.31 (m, 13H), 7.22(d, 1H, J=8.6 Hz), 7.10 (d, 1H, J=2.2 Hz), 6.81 (dd, 1H, J=8.6 Hz, 2.2Hz), 5.23 (s, 2H), 5.11 (s, 2H), 2.34 (s, 3H); MS eI m/z 437 (M+); CHNcalcd for C₂₉H₂₄FNO₂.

EXAMPLE NO. 19 5-Benzyloxy-2-(3-methoxy-phenyl)-3-methyl-1H-indole

Mp=107-109° C.; ¹H NMR (DMSO) 11.00 (s, 1H), 7.51-7.48 (m, 2H),7.43-7.20 (m, 7H), 7.13-7.12 (d, 1H, J=2.1 Hz), 6.93-6.90 (dd, 1H, J=2.3Hz, J=5.7 Hz), 6.86-6.82 (dd, 1H, J=2.3 Hz, J=6.3 Hz), 5.12 (s, 2H),3.83 (s, 3H), 2.38 (s, 3H); IR (KBr) 3400, 2900, 1600 cm⁻¹; MS eI m/z343 (M+); CHN calcd for C₂₃H₂₁NO₂.

EXAMPLE NO. 205-Benzyloxy-3-methyl-2-(4-trifluoromethoxy-phenyl)-1H-indole

Mp=127-128° C.; ¹H NMR (DMSO) 11.07 (s, 1H), 7.77-7.74 (dd, 2H, J=1.8Hz, J=5.0 Hz), 7.50-7.48 (d, 4H, J=8.3 Hz), 7.42-7.25 (m 4H), 7.14-7.13(d, 1H, J=2.2 Hz), 6.87-6.83 (dd, 1H, J=2.3 Hz, J=6.3 Hz), 5.13 (s, 2H),2.37 (s, 3H); IR (KBr) 3360, 1600 cm⁻¹; MS eI m/z 396 (M+); CHN calcdfor C₂₃H₁₈F₃NO₂.

3-Methylindole acetic acid ethyl esters

TABLE 2

Example No. X Q No. 21 H H No. 22 OBn H No. 23 OBn 4′-OMe No. 24 OMe4′-OMe No. 25 OBn 4′-OEt No. 26 OBn 4′-OBn No. 27 OBn 4′-F No. 28 OBn3′-OMe, 4 -OBn No. 29 OBn 4′-O-iPr No. 30 OBn 3′,4′-OCH₂O— No. 31 OBn4′-OCp No. 32 OBn 4′-CF₃ No. 33 OBn 4′-Cl No. 34 OBn 2′-OMe, 4′-OMe

Experimental Procedure for 3-Methylindole Acetic Acid Ethyl EstersSynthesis Method 3 Illustrated for Example No. 26{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

A solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole(indole example No. 7) (32 g, 77 mmol) in DMF (0.15 L) was cooled to 0°C. and treated with sodium hydride (2.2 g, 89 mmol). The reaction wasstirred for 20 minutes and then the benzyl chloride CAS No. [80494-75-3](29 g, 127 mmol) was added and the reaction stirred for 18 hours at roomtemperature. The reaction mixture was poured into water and extractedwith ethyl acetate. The ethyl acetate was washed with brine and driedover magnesium sulfate. The ethyl acetate was concentrated andtriturated with ether to obtain 21 g of a white solid. The filtrate wasconcentrated and triturated with ether to give an additional 7 g ofwhite solid for a total yield of 28 g: Mp=129-131° C.; ¹H NMR (DMSO)7.47 (d, 4H, J=7.2 Hz), 7.39 (q, 4H, J=7.9 Hz), 7.36-7.32 (m, 1H), 7.29(d, 2H, J=8.8 Hz), 7.19 (d, 1H, J=9.0 Hz), 7.13-7.09 (m, 4H), 6.80 (dd,1H, J=8.8, 2.4 Hz), 6.73 (s, 4H), 5.16 (s, 2H), 5.13 (s, 2H), 5.11 (s,2H), 4.66 (s, 2H), 4.11 (q, 2H, J=7.2 Hz), 2.15 (s, 3H), 1.16 (t, 3H,J=7.2 Hz); MS eI m/z 612.

Physical Data for Indole Ethyl Esters

The following indole alkylation products were prepared according toscheme 9 using method 3 with the appropriately substituted 3-methylindole selected from (No. 1-No. 16) as the starting material.

EXAMPLE NO. 21 {4-[2-Phenyl-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Oil; ¹H NMR (DMSO) 7.57-7.30 (m, 7H), 7.13-7.02 (m, 2H), 6.77-6.70 (m,4H), 5.22 (s, 2H), 4.65 (s, 2H), 4.09 (q, 2H, J=7.2 Hz), 2.20 (s, 3H),1.15 (t, 3H, J=7.0 Hz); MS eI m/z 399 (M+).

EXAMPLE NO. 22{4-[5-Benzyloxy-2-phenyl-3-methyl-indol-1-ylmethyl]-phenoxy}-acetic acidethyl ester

Oil; ¹H NMR(DMSO) 7.50-7.40 (m, 10H), 7.22 (d, 1H, J=8.4 Hz), 7.14 (d,1H, J=2.5 Hz), 6.83 (d, 1H, J=2.5 Hz), 6.72 (s, 4H), 5.18 (s, 2H), 5.11(s, 2H), 4.65 (s, 2H), 4.10 (q, 2H, J=7.2 Hz), 2.16 (s, 3H), 1.14 (t,3H, J=7.0 Hz); MS eI m/z 505 (M+).

EXAMPLE NO. 23{4-[5-Benzyloxy-2-(4-methoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Mp=90-96° C.; ¹H NMR (DMSO) 7.47 (d, 2H, J=6.8 Hz), 7.41-7.37 (m, 2H),7.33-7.27 (m, 3H), 7.19 (d, 1H, J=8.8 Hz), 7.12 (d, 1H, J=2.4 Hz), 7.03(d, 2H, J=8.8 Hz), 6.80 (dd, 1H, J=8.8 Hz, 2.4 Hz), 6.74 (s, 4H), 5.16(s, 2H), 5.11 (s, 2H), 4.65 (s, 2H), 4.11 (q, 2H, J=7.0 Hz), 3.79 (s,3H), 2.15 (s, 3H), 1.16 (t, 3H, J=7.0 Hz); IR (KBr) 2990, 2900, 1760,1610 cm−1; MS FAB m/z 536 (M+H+).

EXAMPLE NO. 24{4-[5-Methoxy-2-(4-methoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Mp=109-113° C.; ¹H NMR (DMSO) 7.27 (d, 2H, J=8.8 Hz), 7.17 (d, 1H, J=8.8Hz), 7.03 (d, 2H J=8.6 Hz), 6.99 (d, 1H, J=2.5 Hz), 6.78-6.70 (m, 5H),5.15 (s, 2H), 4.65 (s, 2H), 4.11 (q, 2H, J=7.0 Hz), 3.78 (s, 3H), 3.76(s, 3H), 2.15 (s, 3H), 1.15 (t, 3H, J=7.1 Hz); MS eI m/z 459 (M+).

EXAMPLE NO. 25{4-[5-Benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Mp=113-115° C.; ¹H NMR (DMSO) 7.45 (d, 2H, J=7.3 Hz), 7.40-7.25 (m, 5H),7.17 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.2 Hz), 7.01 (d, 2H, J=6.8 Hz),6.78 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 6.73 (s, 4H), 5.15 (s, 2H), 5.10 (s,2H), 4.65 (s, 2H), 4.15-4.01 (m, 4H), 2.14 (s, 3H), 1.33 (t, 3H, J=5.7Hz), 1.16 (t, 3H, J=7.1 Hz); MS eI m/z 549 (M+).

EXAMPLE NO. 27{4-[5-Benzyloxy-2-(4-flouro-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

¹H NMR (DMSO) 7.50-7.15 (m, 16H), 5.20 (s, 2H), 5.12 (s, 2H), 4.62 (s,2H), 4.13 (q, 2H, J=7.1 Hz), 2.18 (s, 3H), 1.20 (t, 3H, J=7.1 Hz).

EXAMPLE NO. 28{4-[5-Benzyloxy-2-(3-methoxy-4-benzyloxy)-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Foam; ¹H NMR (DMSO) 7.50-7.30 (m, 10H), 7.22 (d, 2H, J=9.1 Hz), 7.13 (d,2H, J=8.6 Hz), 6.85-6.70 (m, 6H), 5.17 (s, 2H), 5.13 (s, 2H), 5.11 (s,2H), 4.66 (s, 2H), 4.14 (m 2H), 3.61 (s, 3H), 2.17 (s, 3H), 1.16 (t, 3H,J=7.0 Hz).

EXAMPLE NO. 29{4-[5-Benzyloxy-2-(4-isopropoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Oil; ¹H NMR (DMSO) 7.46 (d, 2H, J=7.7 Hz), 7.42-7.28 (m, 3H), 7.25 (d,2H, J=8.7 Hz), 7.17 (d, 1H, J=8.7 Hz), 7.11 (d, 1H, J=2.4 Hz), 6.99 (d,2H, J=8.6 Hz), 6.79 (dd, 1H, J=2.4 Hz, 8.8 Hz), 6.73 (s, 4H), 5.15 (s,2H), 5.10 (s, 2H), 4.70-4.60 (m, 3H), 4.10 (q, 2H, J=7.0 Hz), 2.15 (s,3H), 1.27 (d, 6H, J=5.9 Hz), 1.16 (t, 3H, J=7.1 Hz); MS eI m/z 563 (M+).

EXAMPLE NO. 30{4-[5-Benzyloxy-2-(3,4-methlyenedioxy-benzyloxy)-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Oil; ¹H NMR (DMSO) 7.45 (d, 2H, J=7.0 Hz), 7.37 (m, 2H), 7.32 (m, 1H),7.19 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.2 Hz), 7.00 (d, 1H, J=7.9 Hz),6.90 (d, 1H, 5.0 Hz), 6.82-6.75 (m, 6H), 6.07 (s, 2H), 5.16 (s, 2H),5.10 (s, 2H), 4.65 (s, 2H), 4.10 (m, 2H), 2.15 (s, 3H), 1.15 (t, 3H,J=7.0 Hz); MS eI m/z 549 (M+).

EXAMPLE NO. 31{4-[5-Benzyloxy-2-(4-cyclopentyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Mp=96-98° C.; ¹H NMR (DMSO) 7.47 (d, 1H, J=7.2 Hz), 7.40-7.36 (m, 2H),7.33-7.30 (m, 1H), 7.26 (m, 2H), 7.18 (d, 1H, J=8.8 Hz), 7.11 (d, 1H,J=2.4 Hz), 6.98 (d, 2H, J=8.8 Hz), 6.79 (dd, 1H, J=8.8 Hz, 2.4 Hz), 6.74(s, 5H), 5.15 (s, 2H), 5.11 (s, 2H), 4.86-4.80 (m, 1H), 4.66 (s, 2H),4.13 (q, 2H, J=7.2 Hz), 2.15 (s, 3H), 1.98-1.85 (m, 2H), 1.79-1.65 (m,4H), 1.62-1.55 (m, 2H), 1.16 (t, 3H, J=7.0 Hz); IR (KBr) 2950, 2910,2890, 1760, 1610 cm⁻¹; MS eI m/z 589 (M+); CHN calcd for C, 77.39; H,6.67 N, 2.38 Found: C, 76.76; H, 6.63 N, 2.27.

EXAMPLE NO. 32{4-[5-Benzyloxy-3-methyl-2-(4-trifluoromethyl-phenyl)-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Mp=221° C.; ¹H NMR (DMSO) 7.83 (d, 2H, J=8.1 Hz), 7.60 (d, 2H, J=7.9Hz), 7.48 (d, 2H, J=8.4 Hz), 7.40-7.36 (m, 4H), 7.18 (d, 1H, J=2.4 Hz),6.86 (dd, 1H, J=8.8 Hz, 2.4 Hz), 6.72 (s, 4H), 5.21 (s, 2H), 5.12 (s,2H), 4.65 (s, 2H), 4.11 (q, 2H, J=7.2 Hz), 2.20 (s, 3H), 1.16 (t, 3H,J=7.0 Hz); IR (KBr) 2920, 1730 cm−1; MS eI m/z 573 (M+); CHN calcd forC₃₄H₃₀F₃NO₄+0.25H₂O.

EXAMPLE NO. 33{4-[5-Benzyloxy-2-(4-chlorophenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Mp=99-101° C.; ¹H NMR (DMSO) 7.52 (d, 2H, J=8.6 Hz), 7.46 (d, 2H, J=6.8Hz), 7.42-7.38 (m, 4H), 7.36 (m, 1H), 7.25 (d, 1H, J=9.0 Hz),7.14 (d,1H, J=2.4 Hz), 6.83 (dd, 1H, J=8.8 Hz, J=2.5 Hz), 6.72 (s, 4H), 5.18 (s,2H), 5.11(s, 2H), 4.65 (s, 2H), 4.11 (q, 2H, J=7.2 Hz), 2.16 (s, 3H),1.15 (t, 3H, J=7.2 Hz); MS eI m/z 539 (M+); CHN calc for C₃₃H₃₀ClNO₄.

EXAMPLE NO. 34{4-[5-Benzyloxy-2-(2,4-dimethoxy)-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Oil; ¹H NMR (DMSO) 7.30-6.45 (m, 15H), 4.95 (s, 2H), 4.75-4.65 (m, 2H),4.50 (s, 2H), 3.97 (q, 2H, J=7.1 Hz), 3.65 (s, 3H), 3.51 (s, 3H), 1.87(3H), 1.01 (t, 3H, J=7.1 Hz).

3-Methylindole phenylethanols

TABLE 3

Example No. X Q No. 35 H H No. 36 OMe 4′-OMe No. 37 OBn 4′-OEt No. 38OBn 4′-OBn No. 39 OBn 4′-F No. 40 OBn 3′,4′-OCH₂O— No. 41 OBn 4′-O-iPrNo. 42 OBn 4′-OCp No. 43 OBn 4′-CF₃ No. 44 OBn 4′-CH₃ No. 45 OBn 4′-ClNo. 46 OBn 2′-OMe, 4′-OMe

Experimental Procedure for 3-Methylindole Phenethanols Synthesis Method4 Illustrated for Example No. 382-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

A solution of No. 26 from previous step (5.5 g, 8.8 mmol) in THF (50 mL)was cooled to 0° C. and a solution of LiAlH₄ (10 mL, 1 M) in THF wasadded dropwise. After 30 minutes at 0° C. the reaction was carefullyquenched with water, and partitioned between EtOAc and 1 N HCl. TheEtOAc was dried with MgSO₄, concentrated, and chromatographed on silicagel EtOAc/hexane (2:3) to yield 4.0 g of No. 38 as a white foam:

¹H NMR (DMSO) 7.48-7.46 (m, 4H), 7.42-7.27 (m, 8H), 7.20 (d, 1H, J=8.8Hz), 7.12-7.10 (m, 3H), 6.80 (dd, 1H, J=8.8, 2.4 Hz), 6.73 (s, 4H), 5.15(s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 4.80 (t, 1H, J=5.5 Hz), 3.86 (t,2H, J=4.8 Hz), 3.63 (q, 2H, J=5.3 Hz), 2.15 (s, 3H).

Physical Data for Indole Phenethanols

Following compounds were made according to scheme 10 and method 4 usingthe appropriately substituted indole ethyl ester selected from No.21-No. 34.

EXAMPLE NO. 352-{4-[2-phenyl-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

Oil; ¹H NMR (DMSO) 7.57-7.32 (m, 7H), 7.13-7.02 (m, 2H), 6.74 (s, 4H),5.21 (s, 2H), 4.80 (s, 1H), 3.86-3.83 (m, 2H), 3.62 (s, 2H), 2.20 (s,3H); MS eI m/z 357 (M+).

EXAMPLE NO. 362-{4-[5-methoxy-2-(4-methoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

Oil; ¹H NMR (DMSO) 7.27 (d, 2H, J=8.8 Hz),7.17 (d, 1H, J=8.8 Hz), 7.03(d, 2H J=8.6 Hz), 6.99 (d, 1H, J=2.5 Hz), 6.78-6.70 (m, 5H), 5.14 (s,2H), 4.80 (brs, 1H), 3.85 (t, 2H, J=5.0 Hz), 3.78 (s, 3H), 3.76 (s, 3H),3.63 (t, 2H, J=5.0 Hz), 2.16 (s, 3H); MS eI m/z 417 (M+).

EXAMPLE NO. 372-{4-[5-benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

Foam; ¹H NMR (DMSO) 7.45 (d, 2H, J=7.3 Hz), 7.40-7.25 (m, 5H), 7.17 (d,1H, J=8.8 Hz), 7.11 (d, 1H, J=2.2 Hz), 7.01 (d, 2H, J=6.8 Hz), 6.78 (dd,1H, J=8.8 Hz, J=2.4 Hz), 6.73 (s, 4H), 5.15 (s, 2H), 5.10 (s, 2H), 4.80(brs, 1H), 4.06 (q, 2H, J=6.8 Hz), 3.85 (t, 2H, J=5.0 Hz), 3.63 (t, 2H,J=4.8 Hz), 2.14 (s, 3H), 1.33 (t, 3H, =6.9 Hz); MS eI m/z 507 (M+).

EXAMPLE NO. 392-{4-[5-benzyloxy-2-(4-flouro-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

¹H NMR (DMSO) 7.40-6.60 (m, 16H), 5.10 (s, 1H), 5.07 (s, 2H), 5.02 (s,2H), 3.76 (t, 2H, J=4.9 Hz), 3.53 (t, 2H, J=5.0 Hz), 2.06 (s, 3H).

EXAMPLE NO. 402-{4-[5-benzyloxy-2-(3,4-methylenedioxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

Oil; ¹H NMR (DMSO) 7.45 (d, 2H, J=7.0 Hz), 7.37 (m, 2H), 7.32 (m, 1H),7.19 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.2 Hz), 7.00 (d, 1H, J=7.9 Hz),6.90 (d, 1H, 5.0 Hz), 6.82-6.75 (m, 6H), 6.07 (s, 2H), 5.16 (s, 2H),5.10 (s, 2H), 3.86 (t, 2H, J=5.0 Hz), 3.63 (t, 2H, J=5.0 Hz), 2.15 (s,3H); MS eI m/z 507 (M+).

EXAMPLE NO. 412-{4-[5-Benzyloxy-2-(4-isopropoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

Foam; ¹H NMR (DMSO) 7.46 (d, 2H, J=7.7 Hz), 7.42-7.28 (m, 3H), 7.25 (d,2H, J=8.7 Hz), 7.17 (d, 1H, J=8.7 Hz), 7.11 (d, 1H, J=2.4 Hz), 6.99 (d,2H, J=8.6 Hz), 6.79 (dd, 1H, J=2.4 Hz, 8.8 Hz), 6.73 (s, 4H), 5.14 (s,2H), 5.10 (s, 2H), 4.80 (bs, 1H), 4.70-4.60 (m, 1H), 3.85 (t, 2H, J=4.8Hz), 3.63 (t, 2H, J=5.1 Hz), 2.13 (s, 3H), 1.30 (d, 6H, J=5.9 Hz); MS eIm/z 521 (M+).

EXAMPLE NO. 422-{4-[5-Benzyloxy-2-(4-cyclopentyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

Mp=129-131° C.; ¹H NMR (DMSO) 7.47 (d, 2H, J=7.2 Hz), 7.38 (t, 2H, J=7.2Hz), 7.33-7.28 (m, 1H), 7.25 (d, 2H, J=8.8 Hz), 7.18 (d, 1H, J=8.8 Hz),7.11 (d, 1H, J=2.4 Hz), 6.98 (d, 2H, J=8.8 Hz), 6.79 (dd, 1H, J=8.8 Hz,2.4 Hz), 6.74 (s, 4H), 5.15 (s, 2H), 5.11 (s, 2H), 4.84-4.80 (m, 1H),4.79 (t, 1H, J=5.7 Hz), 3.86 (t, 2H, J=4.8 Hz), 3.63 (q, 2H, J=5.1 Hz),2.15 (s, 3H), 1.96-1.87 (m, 2H), 1.77-1.65 (m, 4H), 1.62-1.53 (m, 2H);IR (KBr) 3490 br, 2920, 1620 cm−1; MS eI m/z 547 (M+).

EXAMPLE NO. 432-{4-[5-Benzyloxy-2-(4-trifluoromethyl-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

Foam; ¹H NMR (DMSO) 7.83 (d, 2H, J=8.1 Hz), 7.59 (d, 2H, J=7.9 Hz), 7.47(d, 2H, J=8.3 Hz), 7.42-7.36 (m, 2H), 7.35-7.29 (m, 2H), 7.18 (d, 1H,J=2.4 Hz), 6.87 (dd, 1H, J=8.1 Hz, 2.4 Hz), 6.77-6.68 (m, 4H), 5.21 (s,2H), 5.12 (s, 2H), 4.81 (br s, 1H), 3.85 (t, 2H, J=5.1 Hz), 3.63 (t, 2HJ=5.1 Hz), 2.19 (s, 3H); MS eI m/z 531.

EXAMPLE NO. 442-{4-[5-Benzyloxy-2-(4-methyl-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

Oil; ¹H NMR (DMSO) 7.46 (d, 2H, J=7.2 Hz), 7.45-7.18 (m, 8H), 7.12 (d,1H, J=2.4 Hz), 6.81 (dd, 1H, J=2.4 Hz, 8.6 Hz), 6.73 (s, 4H), 5.15 (s,2H), 5.10 (s, 2H), 4.80 (bs, 1H), 3.85 (t, 2H, J=4.8 Hz), 3.63 (t, 2H,J=4.9 Hz), 2.34 (s, 3H), 2.15 (s, 3H); MS eI m/z 477 (M+).

EXAMPLE NO. 452-{4-[5-Benzyloxy-2-(4-choro-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

Mp=110-113° C.; ¹H NMR (DMSO) 7.52 (d, 2H, J=8.6 Hz), 7.46 (d, 2H, J=6.8Hz), 7.38 (m, 4H), 7.42-7.37 (m, 1H), 7.25 (d, 1H, J=9.0 Hz), 7.14 (d,1H, J=2.4 Hz), 6.83 (dd, 1H, J=8.8 Hz, J=2.5 Hz), 6.76-6.70 (m, 4H),5.17 (s, 2H), 5.11 (s, 2H), 3.85 (t, 2H, J=5.2 Hz), 3.63 (t, 2H, J=5.0Hz), 2.16 (s, 3H); MS eI m/z 497 (M+).

EXAMPLE NO. 462-{4-[5-Benzyloxy-2-(2,4-dimethoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

Oil; ¹H NMR (DMSO) 7.46 (d, 2H, J=7.5 Hz), 7.39-7.35 (m, 2H), 7.31-7.28(m, 1H), 7.16-7.06 (m, 3H), 6.82-6.72 (m, 5H), 6.68 (d, 1H, J=2.2 Hz),6.61 (dd, 1H, J=2.4 Hz, 8.3 Hz), 5.0 (s, 1H), 4.88 (s, 2H), 4.85 (d, 1H,J=6.3 Hz), 4.69 (d, 1H, J=6.3 Hz), 3.63 (t, 2H, J=6.9 Hz), 3.58 (s, 3H),3.46 (s, 3H), 3.40 (t, 2H, J=6.9 Hz), 1.80 (s, 3H).

Data for 3-methylindole phenylethyl bromides

TABLE 4

Example No. X Q No. 47 H H No. 48 OMe 4′-OMe No. 49 OBn 4′-OEt No. 50OBn 4′-OBn No. 51 OBn 4′-F No. 52 OBn 3′, 4′-OCH₂O— No. 52a OBn 3′-OMe,4′-OBn No. 53 ORn 4′-O-iPr No. 54 OBn 4′-OCp No. 55 OBn 4′-CF₃ No. 56OBn 4′-CH₃ No. 57 OBn 4′-Cl

Experimental Procedure for 3-Methylindole Phenethyl bromide SynthesisMethod 5 Illustrated for Example No. 50 EXAMPLE NO. 505-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-1H-indole

To a solution of example No. 38 (3.3 g, 5.8 mmol) in THF (50 mL) wasadded CBr₄ (2.9 g, 8.7 mmol) and PPH₃ (2.3 g, 8.7 mmol). The reactionwas stirred at rt for 3 h and then concentrated and chromatographed onsilica gel using a gradient elution from EtOAc/hexane (1:4) to EtOAc togive 3.2 g of a white solid: Mp=131-134° C.; ¹H NMR (DMSO) 7.64-7.30 (m,10H), 7.29 (d, 2H, J=8.8 Hz), 7.20 (d, 1H, J=8.8 Hz), 7.12-7.09 (m, 3H),6.80 (dd, 1H, J=8.8, 2.4 Hz), 6.77-6.73 (m, 4H), 5.16 (s, 2H), 5.13 (s,2H), 5.11 (s, 2H), 4.20 (t, 2H, J=5.3 Hz), 3.73 (t, 2H, J=5.5 Hz), 2.15(s, 3H); MS FAB 631/633 (M+H⁺, Br present).

Physical Data for Indole Phenethyl Bromides

The following compounds were made according to scheme 11 as described inMethod using the appropriately substituted indole selected from No:35-No. 45.

EXAMPLE NO. 47 1-[4-(2-bromo-ethoxy)-benzyl]-2-phenyl-3-methyl-1H-indole

Oil; ¹H NMR (DMSO) 7.57-7.32 (m, 7H), 7.13-7.02 (m, 2H), 6.74 (s, 4H),5.21 (s, 2H), 4.19 (t, 2H, J=5.2 Hz), 3.71 (t, 2H, J=5.5 Hz), 2.20 (s,3H); MS eI m/z 419 (M+).

EXAMPLE NO. 485-Methoxy-2-(4-methoxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-1H-indole

Oil; ¹H NMR (DMSO) 7.27 (d, 2H, J=8.8 Hz),7.17 (d, 1H, J=8.8 Hz), 7.03(d, 2H J=8.6 Hz), 6.99 (d, 1H, J=2.5 Hz), 6.80-6.69 (m, 5H), 5.14 (s,2H), 4.19 (t, 2H, J=5.4 Hz), 3.78 (s, 3H), 3.76 (s, 3H), 3.72 (t, 2H,J=5.5 Hz), 2.16 (s, 3H); MS eI m/z 479 (M+).

EXAMPLE NO. 495-Benzyloxy-2-(4-ethoxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-1H-indole

Mp=118-120° C.; ¹H NMR (DMSO) 7.45 (d, 2H, J=7.3 Hz), 7.41-7.26 (m, 5H),7.17 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.2 Hz), 7.01 (d, 2H, J=6.8 Hz),6.78 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 6.78-6.74 (m, 4H), 5.15 (s, 2H), 5.10(s, 2H), 4.22-4.18 (m, 2H), 4.04 (q, 2H, J=6.8 Hz), 3.72 (t, 2H, J=5.5Hz), 2.14 (s, 3H), 1.33 (t, 3H, J=7.0 Hz); MS eI m/z 569 (M+).

EXAMPLE NO. 515-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-2-(4-fluoro-phenyl)-3-methyl-1H-indole

Mp=114-116° C.; ¹H NMR (DMSO) 7.47 (m, 2H), 7.45-7.20 (m, 8H), 7.14 (d,1H, J=2.4 Hz), 6.83 (dd, 1H, J=2.7 Hz, 9.0 Hz), 6.80-6.70 (m, 4H), 5.16(s, 2H), 5.11 (s, 2H), 4.19 (t, 2H, J=5.27 Hz), 3.72 (t, 2H, J=6.4 Hz),2.15 (s, 3H); MS eI m/z 543 (M+); CHN calc for C₃₁H₂₇BrFNO₂.

EXAMPLE NO. 522-Benzo[1,3]dioxyl-5-yl-5-benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-1H-indole

Mp=133-136° C.; ¹H NMR (DMSO) 7.45 (d, 2H, J=7.0 Hz), 7.41-7.38 (m, 2H),7.35-7.30 (m, 1H), 7.19 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.2 Hz), 7.00(d, 1H, J=7.9 Hz), 6.90 (d, 1H, 1.4 Hz), 6.82-6.78 (m, 2H), 6.77 (s,4H), 6.07 (s, 2H), 5.16 (s, 2H), 5.10 (s, 2H), 4.20 (t, 2H, J=5.5 Hz),3.73 (t, 2H, J=5.2 Hz), 2.15 (s, 3H); MS eI m/z 569 (M+).

EXAMPLE NO. 52a5-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-2-(3-methoxy-4-benzyloxy-phenyl)-3-methyl-1H-indole

Foam; ¹H NMR (DMSO) 7.47-7.42 (m, 4H), 7.40-7.30 (m, 6H), 7.20 (d, 1H,J=8.8 Hz), 7.12-7.10 (m, 2H), 6.86-6.84 (m, 2H), 6.81 (dd, 1H, J=8.8 Hz,2.4 Hz), 6.78 (s, 4H), 5.17 (s, 2H), 5.11 (s, 2H), 5.10 (s, 2H), 4.20(t, 2H, J=5.0 Hz), 3.72 (t, 2H, J=5.4 Hz), 3.63 (s, 3H), 2.17 (s, 3H);MS FAB m/z 662 (M+H+).

EXAMPLE NO. 535-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-2-(4-isopropoxy-phenyl)-3-methyl-1H-indole

Mp=125-128° C.; ¹H NMR (DMSO) 7.46 (d, 2H, J=7.7 Hz), 7.42-7.28 (m, 3H),7.25 (d, 2H, J=8.7 Hz), 7.17 (d, 1H, J=8.7 Hz), 7.11 (d, 1H, J=2.4 Hz),6.99 (d, 2H, J=8.6 Hz), 6.79 (dd, 1H, J=2.4 Hz, 8.8 Hz), 6.73 (s, 4H),5.14 (s, 2H), 5.10 (s, 2H), 4.70-4.60 (m, 1H), 4.19 (t, 2H, J=5.3 Hz),3.72 (t, 2H, J=4.4 Hz), 2.13 (s, 3H), 1.30 (d, 6H, J=5.9 Hz); MS eI m/z583 (M+).

EXAMPLE NO. 545-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-2-(4-cyclopentyloxy-phenyl)-3-methyl-1H-indole

Mp=110-112° C.; 7.47 (d, 2H, J=7.0 Hz), 7.38 (t, 2H, J=7.0 Hz),7.35-7.28 (m, 1H), 7.25 (d, 2H, J=8.8 Hz), 7.18 (d, 1H, J=8.8 Hz), 7.11(d, 1H, J=2.4 Hz), 6.98 (d, 2H, J=8.6 Hz), 6.79 (dd, 1H, J=8.6 Hz, 2.4Hz), 6.78-6.74 (m, 4H), 5.16 (s, 2H), 5.11 (s, 2H), 4.86-4.83 (m, 1H),4.20 (t, 2H, J=5.3 Hz), 3.73 (t, 2H, J=5.5 Hz), 2.15 (s, 3H), 2.00-1.87(m, 2H), 1.79-1.65 (m, 4H), 1.63-1.56 (m, 2H); IR (KBr) 2950, 2910, 1610cm⁻¹; MS eI m/z 609, 611 (M+, Br present).

EXAMPLE NO. 555-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-2-(4-trifluoromethyl-phenyl)-1H-indole

Mp=106-109° C.; ¹H NMR (DMSO) 7.83 (d, 2H, J=8.1 Hz), 7.60 (d, 2H, J=7.9Hz),7.35-7.29 (m, 2H), 7.48 (d, 2H, J=8.6 Hz), 7.39 (t, 2H, J=7.0 Hz),7.18 (d, 1H, J=2.2 Hz), 6.87 (dd, 1H, J=9.0 Hz, 2.6 Hz), 6.77-6.71 (m,4H), 5.22 (s, 2H), 5.12 (s, 2H), 4.20 (t, 2H, J=5.3 Hz), 3.72 (t, 2H,J=5.3 Hz), 2.20 (s, 3H); IR (KBr) 2910, 2850, 1620 cm−1; MS eI m/z 595,593 (M+)

EXAMPLE NO. 565-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-2-(4-methyl-phenyl)-1H-indole

Mp=82-95° C.; ¹H NMR (DMSO) 7.46 (d, 2H, J=7.2 Hz), 7.45-7.18 (m, 8H),7.12 (d, 1H, J=2.4 Hz), 6.81 (dd, 1H, J=2.4 Hz, 8.6 Hz), 6.73 (s, 4H),5.15 (s, 2H), 5.10 (s, 2H), 4.19 (t, 2H, J=5.3 Hz), 3.72 (t, 2H, J=4.4Hz), 2.34 (s, 3H), 2.15 (s, 3H); MS eI m/z 539 (M+).

EXAMPLE NO. 575-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-2-(4-chloro-phenyl)-1H-indole

¹H NMR (DMSO) 7.52 (d, 2H, J=8.6 Hz),7.46 (d, 2H, J=6.8 Hz), 7.38 (m,4H),7.36 (m, 1H),7.25 (d, 1H, J=9.0 Hz),7.14 (d, 1H, J=2.4 Hz), 6.83(dd, 1H, J=8.8 Hz, J=2.5 Hz), 6.72 (m, 4H), 5.17 (s, 2H), 5.11 (s, 2H),4.19 (t, 2H, J=5.5 Hz), 3.72 (t, 2H, J=5.5 Hz), 2.16 (s, 3H); MS eI m/z559 (M+).

Data for Some 3-Methylindole Phenylethyl Chlorides Used as Intermediates

TABLE 5

Example No. X Q No. 58 OBn 3′-OBn No. 59 OBn 3′-F, 4′-OBn No. 60 OBn4′-OCF₃

Experimental Procedure for 3-Methylindole Phenethylchloride SynthesisMethod 5a Illustrated for Example No. 585-Benzyloxy-2-(3-benzyloxy-phenyl)-1-[4-(2-chloro-ethoxy)-benzyl]-3-methyl-1H-indole

To a solution of 9.7 g (0.0231 mol) of5-benzyloxy-3-methyl-2-(3-benzyloxy-phenyl)-1H-indole (indole exampleNo. 17) in 80 mL of dry DMF was added 0.85 g of sodium hydride (60% inmineral oil). After allowing this mixture to stir for 30 minutes (untilno more bubbling was indicated), 4.8 g of1-chloromethyl-4-(2-chloro-ethoxy)-benzene CAS No. [99847-87-7] wasadded. The reaction mixture was allowed to react at room temperatureovernight. 200 mL of ethyl acetate were added to the reaction mixtureand then washed with water (3×100 mL). The organic solution wascollected, washed with saturated brine, removed, dried over magnesiumsulfate, filtered and evaporated to dryness in a rotary evaporator. Theproduct was recrystallized in ethyl acetate.

Mp=125-127° C.; ¹H NMR (DMSO) 7.48-7.46 (d, 2H, J=6.8 Hz), 7.40-7.35 (m,7H), 7.33-7.28 (m, 2H), 7.23-7.21 (d, 1H, J=8.8 Hz), 7.13-7.12 (d, 1H,J=2.2 Hz), 7.07-7.04 (m, 1H), 6.94-6.92 (d, 2H, J=6.1 Hz), 6.83-6.80(dd, 1H, J=2.5 Hz, J=6.3 Hz), 6.78-6.72 (m, 4H), 5.14 (s, 2H), 5.11 (s,2H), 5.04 (s, 2H), 4.13-4.10 (t, 2H, J=5.1 Hz), 3.86-3.84 (t, 2H, J=5.1Hz), 2.14 (s, 3H); IR 3420, 2900 cm⁻¹; MS eI m/z 587 (M+); CHN calcd forC₃₈H₃₄ClNO₃.

Physical Data for Indole Phenethyl Chlorides

The following compounds were made according to scheme 12 as described inMethod 5a using the appropriately substituted indoles No. 18, No. 20.

EXAMPLE NO. 595-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-1-[4-(2-chloro-ethoxy)-benzyl]-3-methyl-1H-indole

Mp=88-91° C.; ¹H NMR (DMSO) 7.49-7.43 (m, 4H), 7.43-7.28 (m, 7H),7.26-7.21 (m, 2H), 7.13-7.09 (m, 2H), 6.88-6.72 (m, 5H), 5.21 (s, 2H),5.18 (s, 2H), 5.11 (s, 2H), 4.13 (t, 2H, J=5.2 Hz), 3.87 (t, 2H, J=5.2Hz), 2.16 (s, 3H); MS eI m/z 605 (M+); CHN calcd for C₃₈H₃₃ClFNO₃.

EXAMPLE NO. 605-Benzyloxy-1-[4-(2-chloro-ethoxy)-benzyl]-3-methyl-2-(4-trifluoromethoxy-phenyl)-1H-indole

Mp=108-110° C.; ¹H NMR (DMSO) 7.49-7.48 (m, 6H), 7.40-7.25 (m, 4H),7.17-7.16 (d, 1H, J=2.9 Hz), 6.88-6.84 (m, 1H), 6.77-6.72 (m, 4H), 5.20(s, 2H), 5.14-5.13 (d, 2H, J=2.3 Hz), 4.16-4.11 (m, 2H), 3.89-3.84 (m,2H), 2.19-2.17 (m, 3H); IR 3400, 2900, 1600 cm⁻¹; MS eI m/z 566 (M+);CHN calcd for C₃₂H₂₇ClF₃NO₃+0.25H₂₀.

Aminoethoxy Indoles

TABLE 6

Example No. X Q Z No. 61 OBn 4′-OEt

No. 62 OBn H

No. 63 OBn 4′-OBn

No. 64 OBn 4′-OBn

No. 65 OBn 4′-OBn

No. 66 OBn 4′-OBn

No. 66a OBn 4′-OBn

No. 67 OBn 4′-OBn

No. 68 OBn 4′-OBn

No. 69 OBn 4′-OBn

No. 70 OBn 4′-OBn

No. 71 OBn 4′-OBn

No. 71a OBn 4′-OBn

No. 72 OBn 4′-F

No. 72a OBn 4′-F

No. 72b OBn 4′-Cl

No. 73 OBn 3′,4′-OCH₂O—

No. 74 OBn 4′-O-iPr

No. 75 OBn 4′-CH₃

No. 76 OBn 3′-OBn

No. 77 OBn 3′-OBn

No. 78 OBn 4′-OBn, 3′-F

No. 79 OBn 4′-OBn, 3′-F

No. 80 OBn 3′-OMe

No. 81 OBn 4′-OCF₃

No. 82 OBn 4′-OBn

No. 83 OBn 4′-OBn

No. 84 OBn 3′-OMe

Experimental Procedure for 3-Methyl Aminoethoxyindole Synthesis Method 6Illustrated for Example No. 63 Substitution of the Bromide5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

A solution of example No. 50 (3.2 g, 5.0 mmol) in THF (50 mL) wastreated with piperidine (5.0 mL, 50 mmol) and heated to reflux. After 5hours, the reaction mixture was concentrated and taken up in EtOAc,washed with saturated NaHCO₃, dried over MgSO₄ and columnchromatographed on silica gel using a gradient elution of EtOAc/Hexaneto EtOAc. The product (2.7 g) was a white solid with a Mp=93-95° C.; ¹HNMR (DMSO) 7.48-7.46 (m, 4H), 7.42-7.38 (m, 4H), 7.38-7.32 (m, 2H), 7.29(d, 2H, J=8.8 Hz), 7.19 (d, 1H, J=9.0 Hz), 7.12-7.10 (m, 3H), 6.80 (dd,1H, J=8.8, 2.4 Hz), 6.73 (s, 4H), 5.15 (s, 2H), 5.13 (s, 2H), 5.11 (s,2H), 3.93 (t, 2H, J=5.7 Hz), 2.60-2.50 (m, 2H), 2.41-2.30 (m, 4H), 2.15(s, 3H), 1.47-1.42 (m, 4H), 1.36-1.32 (m, 2H); MS FAB 637 (M+H⁺).

Alternative Procedure Method 6a Substitution of Chlorides SynthesisIllustrated for Product No. 76 EXAMPLE NO. 765-Benzyloxy-2-(3-benzyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

To a solution of 1.1 g (0.00953 mol) of5-benzyloxy-2-(3-benzyloxy-phenyl-1-[4-(2-chloro-ethoxy)-benzyl]-3-methyl-1H-indole(example No. 58) in 10 mL of DMF was added 1.1 mL (0.0112 mol) ofpiperidine, and 0.93 g (00561 mol) of potassium iodide. The reactionmixture was heated to ˜40-50° C. for 4 hours. After cooling the reactionmixture to room temperature, 150 mL of ethyl acetate were added and themixture was washed with water (3×100 mL). The organic solution wascollected, washed with saturated brine, removed, dried over magnesiumsulfate, filtered and evaporated to yield 1.0 g of product of theproduct after purification.

Mp=125-126° C.; ¹H NMR (DMSO) 7.48-7.45 (d, 2H, J=7.2 Hz), 7.41-7.35 (m,7H), 7.33-7.28 (m, 2H), 7.23-7.21 (d, 1H, J=9.0 Hz), 7.13-7.12 (d, 1H,J=2.4 Hz), 7.06-7.03 (m, 1H), 6.95-6.91 (m, 2H), 6.83-6.80 (dd, 1H,J=2.4 Hz, J=6.3 Hz), 6.75-6.70 (m, 4H), 5.13 (s, 2H), 5.11 (s, 2H), 5.02(s, 2H), 3.93-3.90 (t, 2H, J=6.0 Hz), 2.56-2.53 (t, 2H, J=5.9 Hz),2.49-2.48 (m, 4H), 2.14 (s, 3H), 1.46-1.40 (m, 4H), 1.35-1.31 (m, 2H);IR (KBr) 3400, 2900 cm⁻¹; MS eI m/z 636 (M+); CHN calcd forC₄₃H₄₄N₂O₃+0.25H₂O.

Physical Data for the Amine Substituted Compounds

The following compounds were prepared by scheme 13 using method 6.Except for examples No. 76-No. 84 which were prepared using method 6a.

EXAMPLE NO. 615-Benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

Mp=188-191° C.; ¹H NMR (DMSO) 7.45 (d, 2H, J=7.3 Hz), 7.40-7.25 (m, 5H),7.17 (d 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.2 Hz), 7.01 (d, 2H, J=6.8 Hz),6.78 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 6.73 (s, 4H), 5.15 (s, 2H), 5.10 (s,2H), 4.05 (q, 2H, J=6.8 Hz), 3.93 (t, 2H, J=6.0 Hz), 2.55 (t, 2H, J=5.7Hz), 2.41-2.35 (m, 4H), 2.14 (s, 3H), 1.46-1.40 (m, 4H), 1.38-1.30 (m,5H); MS eI m/z 574 (M+).

EXAMPLE NO. 625-Benzyloxy-2-phenyl-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole

Oil; ¹H NMR (DMSO) 7.50-7.43 (m, 4H), 7.42-7.37 (m, 5H), 7.33-7.30(m,1H), 7.22 (d, 1H, J=8.8 Hz), 7.14 (d, 1H, J=2.4 Hz), 6.81 (d, 1H, J=6.6Hz), 6.72 (s, 4H), 5.18 (s, 2H), 5.11 (s, 2H), 3.90 (t, 2H, J=6.1 Hz),2.81-2.75 (m, 2H), 2.68-2.59 (m, 4H), 2.16 (s, 3H), 1.58-1.43 (m, 8H);MS eI m/z 544 (M+).

EXAMPLE NO. 645-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole

Mp=106-107° C.; ¹H NMR (DMSO) 7.47 (d, 4H, J=8.3 Hz), 7.41-7.36 (m, 4H),7.36-7.30 (m, 2H), 7.29 (d, 2H, J=8.8 Hz), 7.19 (d, 1H, J=8.8 Hz),7.14-7.10 (m, 3H), 6.80 (dd, 1H, J=8.8 Hz), 6.73 (s, 4H), 5.15 (s, 2H),5.13 (s, 2H), 5.11 (s, 2H), 3.90 (t, 2H, J=5.9 Hz), 2.76 (t, 2H, J=5.9Hz), 2.64-2.56 (m, 4H), 2.15 (s, 3H), 1.58-1.44 (m, 8H); MS FAB m/z 651(M+H+).

EXAMPLE NO. 655-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-diisopropylamino-1-yl-ethoxy)-benzyl]-1H-indole

Mp=148-150° C.; ¹H NMR (DMSO) 7.47 (d, 4H, J=8.3 Hz), 7.41-7.36 (m, 4H),7.36-7.32 (m, 2H), 7.28 (d, 2H, J=8.8 Hz), 7.19 (d, 1H, J=9.0 Hz),7.13-7.08 (m, 3H), 6.80 (dd, 1H, J=8.8 Hz, 2.4 Hz), 6.76-6.68 (m, 4H),5.14 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 3.75 (t, 2H, J=7.0 Hz), 2.95(m, 2H), 2.67 (t, 2H, J=7.0 Hz), 2.15 (s, 3H), 0.93 (d, 12H, J=6.4 Hz);MS FAB m/z 653 (M+H+).

EXAMPLE NO. 665-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-butyl-methylamino-1-ylethoxy)-benzyl]-1H-indole

Mp=101-104° C.; ¹H NMR (DMSO) 7.45 (d, 4H, J=7.5 Hz), 7.40-7.25 (m, 8H),7.19 (d, 1H, J=8.8 Hz), 7.12-7.08 (m, 3H), 6.80 (dd, 1H, J=6.5 Hz, J=2.4Hz), 6.72 (s, 4H), 5.14 (s, 2H), 5.13 (s, 2H), 5.10 (s, 2H), 3.91 (t,2H, J=5.9 Hz), 2.64-2.59 (m, 2H), 2.35-2.29 (m, 2H), 2.17 (s, 3H), 2.14(s, 3H), 1.40-1.31 (m, 2H), 1.25-1.19 (m, 2H), 0.83 (t, 3H, 7.2 Hz); MSelm/z 638 (M+).

EXAMPLE NO. 66a5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-dimethylamino)-ethoxy]-benzyl}-1H-indole

Mp=123-124° C.

EXAMPLE NO. 675-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indole

Mp=121° C.

EXAMPLE NO. 685-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(3-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indole

Mp=90° C.

EXAMPLE NO. 695-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indole

Mp=98° C.; ¹H NMR (DMSO) 7.46 (d, 4H, J=7.2 Hz), 7.42-7.36 (m, 4H),7.36-7.31 (m, 2H), 7.28 (d, 2H, J=8.6 Hz), 7.19 (d, 1H, J=9.0 Hz),7.12-7.10 (m, 3H), 6.80 (dd, 1H, J=8.8 Hz, 2.4 Hz), 6.73 (s, 4H), 5.15(s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 3.93 (t, 2H, J=5.9 Hz), 2.85-2.78(m, 2H), 2.62-2.56 (m, 2H), 2.15 (s, 3H), 1.97-1.87 (m, 2H), 1.55-1.47(m, 2H), 1.30-1.20 (m, 1H), 1.15-1.02 (m, 2H), 0.85 (d, 3H, J=6.6 Hz);MS esI m/z 651 (M+1)+.

EXAMPLE NO. 70 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1{4-[2-((cis)-2,6-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indole

Mp=106-107° C.; ¹H NMR (DMSO) 7.46 (d, 4H, J=8.1 Hz), 7.42-7.36 (m, 4H),7.37-7.31 (m, 2H), 7.29 (d, 2H, J=8.8 Hz), 7.18 (d, 1H, J=8.8 Hz),7.14-7.09 (m, 3H), 6.80 (dd, 1H, J=8.8 Hz, 2.4 Hz), 6.72 (s, 4H), 5.14(s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 3.84 (t, 2H, J=7.0 Hz), 2.84 (t,2H, J=6.6 Hz), 2.44-2.37 (m, 2H), 2.15 (s, 3H), 1.60-1.43 (m, 3H),1.32-1.18 (m, 1H), 1.16-1.06 (m, 2H), 1.01 (d, 6H, J=6.2 Hz).

EXAMPLE NO. 715-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-{4-[2-(1,33-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-ethoxy]-benzyl}-1H-indole

Mp=107° C.; MS ESI m/z 705 (M+1)+

EXAMPLE NO. 71a(1S,4R)-5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-{4-[2-(2-Aza-bicyclo[2.2.1] hept-2-yl)-ethoxy]-benzyl}-1H-indole

The (1S,2R)-2-aza-bicyclo [2.2.1] heptane used to substitute the bromidewas prepared according to the procedure outlined in Syn. Comm. 26(3),577-584 (1996).

Mp=95-100° C.; ¹H NMR (DMSO) 7.32-6.55 (m, 21H), 5.10-4.90 (m, 6H), 3.69(t, 2H, J=5.9 Hz), 2.65-2.5 (m, 3H), 2.10 (s, 2H), 2.0 (s, 3H), 1.50-1.0(m, 7H).

EXAMPLE NO. 725-Benzyloxy-2-(4-flouro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole

Oil; ¹H NMR (DMSO) 7.50-7.43 (m, 2H), 7.42-7.33 (m, 4H), 7.32-7.20 (m,4H), 7.13 (d, 1H, J=2.4 Hz), 6.83 (dd, 1H, J=2.4 Hz, 6.7 Hz), 6.71 (s,4H), 5.14 (s, 2H), 5.11 (s, 2H), 3.89 (t, 2H, J=5.9 Hz), 3.20 (m, 4H),2.74 (t, 2H, J=6.0 Hz), 2.15 (s, 3H), 1.60-1.40 (m, 8H); MS eI m/z 562(M+).

EXAMPLE NO. 72a5-Benzyloxy-2-(4-flouro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

Oil; ¹H NMR (DMSO) 7.32-6.53 (m, 16H), 5.00 (s, 2H), 4.96 (s, 2H), 3.77(t, 2H, J=5.8 Hz), 3.22-3.14 (m, 4H), 2.40 (t, 2H, J=5.8 Hz), 2.0 (s,3H), 1.29-1.17 (m, 6H).

EXAMPLE NO. 72b5-Benzyloxy-2-(4-chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

Oil; ¹H NMR (DMSO) 7.52 (d, 2H, J=8.6 Hz), 7.46 (d, 2H, J=6.8 Hz),7.41-7.37 (m, 4H), 7.35-7.29 (m, 1H), 7.25 (d, 1H, J=9.0 Hz), 7.14 (d,1H, J=2.4 Hz), 6.83 (dd, 1H, J=8.8 Hz, 2.5 Hz), 6.72-6.65 (m, 4H), 5.16(s, 2H), 5.11 (s, 2H), 3.90 (t, 2H, J=5.9 Hz), 2.55 (t, 2H, J=6.0 Hz),2.41-2.26 (m, 4H), 2.16 (s, 3H), 1.44-1.39 (m, 4H), 1.38-1.29 (m, 2H);MS eI m/z 564 (M+).

EXAMPLE NO. 735-Benzyloxy-2-[3,4-methylenedioxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

Foam; ¹H NMR (DMSO) 7.45 (d, 2H, J=7.0 Hz), 7.41-7.37 (m, 2H), 7.33-7.29(m, 1H), 7.19 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.2 Hz), 7.00 (d, 1H,J=7.9 Hz), 6.90 (d, 1H, 1.4 Hz), 6.82-6.78 (m, 2H), 6.74 (s, 4H), 6.07(s, 2H), 5.16 (s, 2H), 5.10 (s, 2H), 3.93 (t, 2H, J=6.0 Hz), 2.56 (t,2H, J=6.0 Hz), 2.41-2.35 (m, 4H), 2.15 (s, 3H), 1.48-1.41 (m, 4H),1.38-1.28 (m, 2H); MS eI m/z 574 (M+).

EXAMPLE NO. 745-Benzyloxy-2-[4-isopropoxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

Foam; ¹H NMR (DMSO) 7.46 (d, 2H, J=7.7 Hz), 7.42-7.28 (m, 3H), 7.25 (d,2H, J=8.7 Hz), 7.17 (d, 1H, J=8.7 Hz), 7.11 (d, 1H, J=2.4 Hz), 6.99 (d,2H, J=8.6 Hz), 6.79 (dd, 1H, J=2.4 Hz, 8.8 Hz), 6.73 (s, 4H), 5.14 (s,2H), 5.10 (s, 2H), 4.70-4.60 (m, 1H), 3.92 (t, 2H, J=5.7 Hz), 2.55 (t,2H, 5.7 Hz), 2.40-2.30 (bs, 4H), 2.15 (s, 3H), 1.50-1.40 (m, 4H),1.40-1.30 (m, 2H), 1.28 (d, 6H, J=6.2 Hz); MS eI m/z 588 (M+).

EXAMPLE NO. 755-Benzyloxy-2-[4-methyl-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

Oil; ¹H NMR (DMSO) 7.46 (d, 2H, J=7.2 Hz), 7.45-7.18 (m, 8H), 7.12 (d,1H, J=2.4 Hz), 6.81 (dd, 1H, J=2.4 Hz, 8.6 Hz), 6.73 (s, 4H), 5.15 (s,2H), 5.10 (s, 2H), 3.92 (t, 2H, J=5.9 Hz), 2.55 (t, 2H, J=5.9 Hz),2.45-2.30 (m, 7H), 2.10 (s, 3H), 1.50-1.40 (m, 4H), 1.48-1.35 (m, 2H);MS eI m/z 544 (M+).

EXAMPLE NO. 771-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-benzyloxy-phenyl)-3-methyl-1H-indole

Mp=103-105° C.; ¹H NMR (DMSO) 7.47-7.45 (d, 2H, J=8.1 Hz), 7.41-7.35 (m,7H), 7.32-7.29 (t, 2H, 7.0 Hz), 7.23-7.21 (d, 1H, J=8.7 Hz), 7.13-7.12(d, 1H, J=2.1 Hz), 7.06-7.03 (m, 1H), 6.95-6.91 (m, 2H), 6.83-6.80 (m,1H), 6.75-6.73 (m, 4H), 5.13 (s, 2H), 5.11 (s, 2H), 5.02 (s, 2H),3.90-3.87 (t, 2H, J=6.0 Hz), 2.76-2.73 (t, 2H, J=6.0 Hz), 2.49-2.48 (m,4H), 2.13 (s, 3H), 1.51 (s, 8H); IR 3400, 2900 cm⁻¹; MS eI m/z 650 (M+);CHN calcd for C₄₄H₄₆N₂O₃.

EXAMPLE NO. 785-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

Mp=125-128° C.; ¹H NMR (DMSO) 7.50-7.45 (m, 4H), 7.43-7.28 (m, 7H),7.26-7.20 (m, 2H), 7.14-7.09 (m, 2H), 6.82 (dd, 1H, J=2.4 Hz, 8.8 Hz),6.72 (s, 4H), 5.21 (s, 2H), 5.16 (s, 2H), 5.11 (s, 2H), 3.94 (t, 2H,J=5.8 Hz), 2.62-2.56 (m, 2H), 2.41-2.36 (m, 4H), 2.15 (s, 3H), 1.45-1.40(m, 4H), 1.40-1.31 (m, 2H); MS eI m/z 654 (M+); CHN calcd forC₄₃H₄₃FN₂O₃.

EXAMPLE NO. 795-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole

Mp=122-124° C.; ¹H NMR (DMSO) 7.50-7.28 (m, 10H), 7.26-7.20 (m, 2H),7.15-7.10 (m, 2H), 6.88-6.76 (m, 2H), 6.70 (s, 4H), 5.22 (s, 2H), 5.16(s, 2H), 5.11 (s, 2H), 3.92-3.86 (m, 2H), 2.82-2.65 (m, 2H), 2.65-2.55(m, 4H), 2.15 (s, 3H), 1.60-1.4 (m, 8H); MS eI m/z 668 (M+); CHN calcdfor C₄₄H₄₅FN₂O₃.

EXAMPLE NO. 805-Benzyloxy-2-(3-methoxy-phenyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-methyl-1H-indole

Mp 86-87° C.; ¹H NMR (DMSO) 7.50-7.49 (m, 2H), 7.46-7.31 (m, 4H),7.24-7.21 (d, 1H, J=8.8 Hz), 7.15-7.14 (d, 1H, J=2.3 Hz), 7.00-6.93 (m,2H), 6.88-6.81 (m, 2H), 6.75 (s, 4H), 5.18 (s, 2H), 5.12 (s, 2H),3.96-3.92 (t, 2H, J=5.9 Hz), 3.71 (s, 3H), 2.59-2.55 (t, 2H, J=5.8 Hz),2.37 (s, 4H), 2.18 (s, 3H), 1.49-1.42 (m, 4H), 1.37-1.34 (m, 2H); MS eIm/z 561 (M+); CHN calcd for C₃₇H₄₀N₂O₃+0.25H₂O.

EXAMPLE NO. 815-Benzyloxy-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethoxy-phenyl)-1H-indole

Mp=107-108° C.; ¹H NMR (DMSO) 7.52-7.45 (m, 6H), 7.41-7.26 (m, 4H),7.17-7.16 (d, 1H, J=2.3 Hz), 6.87-6.84 (dd, 1H, J=2.3 Hz, J=6.4 Hz),6.75-6.68 (m, 4H), 5.18 (s, 2H), 5.13 (s, 2H), 3.95-3.91 (t, 2H, J=5.9Hz), 2.58-2.54 (t, 2H, J=5.9 Hz), 2.38-2.34 (m, 4H), 2.17-2.15 (s, 3H),1.49-1.42 (m, 4H), 1.35-1.34 (d, 2H, J=4.9 Hz); IR 3400, 2900, 1600cm⁻¹; MS eI m/z 615 (M+); CHN calcd for C₃₇H₃₇F₃N₂O₃.

EXAMPLE NO. 82(2-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethyl)-cyclohexyl-amine

Mp=87-90° C.; ¹H NMR (DMSO) 7.46(dd, 4H, J=6.9 Hz, 0.6 Hz), 7.42-7.27(m, 9H), 7.19 (d, 1H, J=9 Hz), 7.14-7.08 (m, 3H), 6.80 (dd, 1H, J=6.4Hz, 2.4 Hz), 6.75-6.70 (m, 4H), 5.15(s, 2H), 5.13 (s, 2H), 5.13(s, 2H),3.89 (t, 2H, J=5.6), 2.84 (m, 2H), 2.48 (m, 1H), 2.14 (s, 3H), 1.80 (m,2H), 1.65 (m, 2H), 1.61 (m, 1H), 0.96-1.19 (m, 5H); MS eI m/z 650 (M+);CHN calcd for C₄₄H₄₆N₂O₄.

EXAMPLE NO. 835-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-methylpiperazin-1-yl)-ethoxy]-benzyl}-1H-indole

Mp=88-91° C.; ¹H NMR (DMSO) 7.47 (m, 4H), 7.26-7.42 (m, 8H), 7.19 (d,1H, J=8.8), 7.10-1.12 (m, 3H), 6.80 (q, 1H, J=6.3 Hz, 2.4 Hz), 6.73 (m,4H), 5.15 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 3.94 (t, 2H, J=5.9 Hz),2.59 (t, 2H), 2.42 (m, 4H), 2.29 (m, 4H), 2.15 (s, 3H), 2.12 (s, 3H); MSeI m/z 652 (M+); CHN calcd for C₄₃H₄₅N₃O₃.

EXAMPLE NO. 841-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-methoxy-phenyl)-3-methyl-1H-indole

Mp=103-105° C.; ¹H NMR (DMSO) 7.47-7.45 (d, 2H, J=8.1 Hz), 7.41-7.35 (m,7H), 7.32-7.29 (t, 2H, 7.0 Hz), 7.23-7.21 (d, 1H, J=8.7 Hz), 7.13-7.12(d, 1H, J=2.1 Hz), 7.06-7.03 (m, 1H), 6.95-6.91 (m, 2H), 6.83-6.80 (m,1H), 6.75-6.73 (m, 4H), 5.13 (s, 2H), 5.11 (s, 2H), 5.02 (s, 2H),3.90-3.87 (t, 2H, J=6.0 Hz), 2.76-2.73 (t, 2H, J=6.0 Hz), 2.49-2.48 (m,4H), 2.13 (s, 3H), 1.51 (s, 8H); IR 3400, 2900 cm⁻¹; MS eI m/z 650 (M+);CHN calcd for C₄₄H₄₆N₂O₃.

Data and Procedures for Compounds from Table 11 (ER Receptor Data Table,Infra) of Text

TABLE 7

Example No. X Q Z No. 85 H H

No. 86 H 4′-OH

No. 87 OH H

No. 88 OMe 4′-OH

No. 89 OH 4′-OMe

No. 90 OMe 4′-OMe

No. 91 OMe 4′-OMe

No. 92 OH 4′-OEt

No. 93 OH 4′-OEt

No. 94 F 4′-OH

No. 95 OH H

No. 96 OH 4′-OH

No. 97 OH 4′-OH

No. 98 OH 4′-OH

No. 99 OH 4′-OH

No. 100 OH 4′-OH

No. 101 OH 4′-OH

No. 102 OH 4′-OH

No. 103 OH 4′-OH

No. 104 OH 4′-OH

No. 105 OH 4′-OH

No. 106 OH 4′-OH

No. 107 OH 4′-OH

No. 108 OH 4′-OH

No. 109 OH 4′-OH

No. 110 OH 4′-OH

No. 111 OH 4′-OH

No. 112 OH 4′-OH

No. 113 OH 4′-OH

No. 114 OH 4′-OH

No. 115 OH 4′-OH

No. 116 OH 4′-F

No. 117 OH 4′-F

No. 118 OH 3′-OMe, 4′-OH

No. 119 OH 3′,4′-OCH₂O—

No. 120 OH 4′-O-iPr

No. 121 OH 4′-O-iPr

No. 122 OH 4′-O-Cp

No. 123 OH 4′-CF₃

No. 124 OH 4′-CH₃

No. 125 OH 4′-Cl

No. 126 OH 2′,4′,-Dimethoxy

No. 127 OH 3′-OH

No. 128 OH 3′-OH

No. 129 OH 4′-OH,3′-F

No. 130 OH 4′-OH, 3′-F

No. 131 OH 3′-OMe

No. 132 OH 4′-OCF₃

Hydrogenation of Indoles Containing Benzyl Ether(s) Method 7 Illustratedfor Example No. 972-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol

A suspension of 10% Pd/C (1.1 g) in EtOH was treated with a solution ofNo. 63 (2.2 g, 3.4 mmol) in THF/EtOH. Cyclohexadiene (6.0 mL, 63 mmol)was added and the reaction was stirred for 48 hours. The catalyst wasfiltered through Celite and the reaction mixture was concentrated andchromatographed on silica gel using a gradient elution of MeOH/CH₂Cl₂(1:19 to 1:10) to yield 0.8 g of the product as a white solid.Mp=109-113° C.; CHN calc'd for C₂₉H₃₂N₂O₃+0.5H₂O; ¹H NMR 9.64 (s, 1H),8.67 (s, 1H), 7.14 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=8.6 Hz), 6.84 (d,2H, J=8.8 Hz), 6.79 (d, 1H, J=2.2 Hz), 6.74 (s, 4H), 6.56 (dd, 1H,J=8.8, 2.4 Hz), 5.09 (s, 2H), 3.95-3.93 (m, 2H), 2.60-2.51 (m, 2H),2.39-2.38 (m, 4H), 2.09 (s, 3H), 1.46-1.45 (m, 4H), 1.35-1.34 (m, 2H);IR (KBr) 3350 (br), 2920, 1620, 1510 cm−1; MS (EI) m/z 456.

Alternatively, the compounds may be dissolved in a THF/EtOH solution (orother appropriate solvent) and hydrogenated with H₂ and 10% Pd/C usingeither a ballon or Parr Hydrogenator. Either procedure is effective. Inmany of the examples, the compounds were made into acid addition salts.The procedure for the preparation of an HCl salt is given below (Method8).

Method 8

1.0 g of Example No. 97 free base from the hydrogenation procedure abovein a large test tube was dissolved in 20 mL of MeOH. This was treatedwith slow addition of 2.6 mL 1.0 N HCl and then 4.0 mL deionized water.The tube was partially opened to the atmosphere to encourage slowevaporation of the solvents. After about ten minutes, crystals began toappear and after 4 hours the solution was filtered and the solidcrystals washed with water. The product was present as 0.42 g of whitecrystalline plates with a melting point of 184-185° C. The mother liquoryielded an additional crop of 0.30 g of white solid with a melting pointof 177-182° C. CHN calc'd for C₂₉H₃₂N₂O₃+HCl+1H₂O.

Alternatively, the compounds can be made into quaternary ammonium salts.An example procedure for the synthesis of example No. 107 is given below(Method 9).

Method 9 EXAMPLE NO. 1072-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-olmethiodide

0.8 g of example No. 97 was dissolved in 18 mL THF and treated with 2 mLof methyl iodide. The solution was heated to reflux for an hour. Thereaction was allowed to come to room temperature and the solids filteredto yield 0.72 g as a crystalline solid.

Mp=214-217° C., CHN calcd for C₂₉H₃₂N₂O₃+CH₃I+0.5H₂O.

EXAMPLE NO. 106

2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-dimethyl-1-yl-ethoxy)-benzyl]-1H-indol-5-olmethiodide was prepared similarly to No. 106 except using No. 100 forstarting material: Mp=245-250° C.; ¹H NMR (DMSO) 9.66 (s, 1H), 8.69 (s,1H), 7.16 (d, 2H, J=8.4 Hz), 7.05 (d, 1H, J=8.8 Hz), 6.84 (d, 1H, J=8.6Hz), 6.81-6.75 (m, 6H), 6.56 (dd, 1H, J=2.4 Hz, 8.7 Hz), 5.12 (s, 2H),4.34 (m, 2H), 3.70 (t, 2H, J=4.6 Hz), 3.11 (s, 9H), 2.09 (s, 3H); IR(KBr) 3250, 1500, 1250; MS eI m/z 416 (M+); CHN calcd forC₂₆H₂₈N₂O₃+1.09 CH₃I+0.8H₂₀.

Physical Data for Final, Deprotected Compounds

The following compounds are either free bases, HCl salts or acetatesalts. They were prepared according to the procedure outlined in method7 using the appropriate benzyl ether for precursor. Where a compoundfrom table 1 does not contain a free phenolic functionality, then it wasunnecessary to debenzylate it and method 7 not applied. The physicaldata for these compounds (No. 85, No. 90-No. 91) is still presentedbelow.

EXAMPLE NO. 854-{3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole} (HCl)

Mp=134-137° C.; ¹H NMR (DMSO) 10.33 (s, 1H), 7.56-7.38 (m, 6H), 7.32 (d,1H, J=8.1 Hz), 7.14-7.0 (m, 2H), 6.80 (s, 4H), 5.24 (s, 2H), 4.28 (t,2H, J=5.0 Hz), 3.50-3.40 (m, 4H), 3.0-2.95 (m, 2H), 2.10 (s, 3H),1.80-1.60 (m, 5H), 1.40-1.35 (m, 1H); IR 3400, 2900, 1510, 1250 cm⁻¹; MS(+) FAB m/z 425 [M+H]⁺; CHN calcd for C₂₉H₃₂N₂O+1.0 HCl+1.0H₂O.

EXAMPLE NO. 864-{3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl}-phenolhydrochloride (HCl)

Mp=192-194° C.; ¹H NMR (DMSO), 10.28 (s, 1H), 9.75 (s, 1H), 7.51-7.49(m, 1H), 7.27 (dd, 1H, J=7.0 Hz, 0.7 Hz), 7.18 (d, 2H, J=7.6 Hz),7.09-7.02 (m, 2H), 6.86 (d, 2H, J=8.6 Hz), 6.80 (s, 4H), 5.20 (s, 2H),4.28 (t, 2H, J=4.9 Hz), 3.50-3.35 (m, 4H), 3.0-2.85 (m, 2H), 2.20 (s,3H), 1.80-1.60 (m, 5H), 1.40-1.30 (m, 1H); IR 3400, 3100, 2600, 1500,1225 cm⁻¹; MS eI m/z 440 (M+); CHN calc for C₂₉H₃₂N₂O₂+1HCl.

EXAMPLE NO. 873-Methyl-2-phenyl-1-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-1H-indol-5-ol(HCl)

Mp=228-230° C.; ¹H NMR 10.1 (brs, 1H), 8.76 (s, 1H), 7.55-7.45 (m,5H),7.10 (d, 1H, J=8.8 Hz), 6.85-6.80 (m, 5H), 6.61 (d, 1H, J=8.8 Hz),5.15 (s, 2H), 4.25 (t, 2H, J=4.8 Hz), 3.47-3.35 (m, 4H), 2.96-2.87 (m,2H), 2.12 (s, 3H), 1.75-1.65 (m, 5H), 1.31-1.28 (m, 1H); MS eI m/z 440(M+); CHN calcd for C₂₉H₃₂N₂O₂+1HCl+0.33H₂O; IR (KBr) 3200, 2500, 1450,1200 cm−1.

EXAMPLE NO. 884-{5-Methoxy-3-methyl-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-2-yl}-phenol

Mp=87-90° C.; ¹H NMR (DMSO) 9.67 (s, 1H), 7.16 (d, 2H, J=8.6 Hz), 7.16(1H buried), 6.98 (d, 1H, J=2.4 Hz), 6.85 (d, 2H, J=8.6 Hz), 6.73 (s,4H), 6.69 (dd, 1H, J=8.8, 2.4 Hz), 5.13 (s, 2H), 3.94 (t, 2H, J=5.7 Hz),3.76 (s, 3H), 2.63-2.50 (m, 2H), 2.43-2.31 (m, 4H), 2.15 (s, 3H),1.49-1.40 (m, 4H), 1.39-1.25 (m, 2H); IR (KBr) 3400 (br), 2920, 1610,1520 cm⁻¹; MS eI m/z 470; CHN calcd for C₃₀H₃₄N₂O₃+0.1H₂O.

EXAMPLE NO. 892-(4-methoxy-phenyl)-3-methyl-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol

Mp=188-189° C.; ¹H NMR (DMSO) 8.70 (s, 1H), 7.27 (d, 2H, J=8.6 Hz), 7.06(d, 1H, J=8.6 Hz), 7.02 (d, 2H, J=8.8 Hz), 6.81 (d, 1H, J=2.2 Hz), 6.73(s, 4H), 6.58 (dd, 1H, J=8.8, 2.4 Hz), 5.10 (s, 2H), 3.93 (t, 2H, J=5.9Hz), 3.79 (s, 3H), 2.56 (t, 2H, J=5.9 Hz), 2.41-2.32 (m, 4H), 2.10 (s,3H), 1.47-1.41 (m, 4H), 1.34-1.31 (m, 2H); MS eI m/z 470; CHN calcd forC₃₀H₃₄N₂O₃+0.1H₂O.

EXAMPLE NO. 905-Methoxy-2-(4-methoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole(HCl)

Mp=188-191° C.; ¹H NMR (DMSO) 10.35 (brs, 1H), 7.27 (d, 2H, J=8.8 Hz),7.17 (d, 1H, J=8.8 Hz), 7.03 (d, 2H J=8.6 Hz), 6.99 (d, 1H, J=2.5 Hz),6.82-6.78 (m, 4H), 6.71 (dd, 1H, J=8.8 Hz, J=2.5 Hz), 5.17 (s, 2H),4.31-4.22 (m, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.43-3.36 (m, 4H),2.97-2.83 (m, 2H), 2.16 (s, 3H), 1.80-1.59 (m, 5H), 1.41-1.26 (m, 1H);IR (KBr) 2920, 1450, 1250 cm−1; MS eI m/z 484 (M+); CHN calc forC₃₁H₃₆N₂O₃+1HCl.

EXAMPLE NO. 911-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-methoxy-2-(4-methoxy-phenyl)-3-methyl-1H-indole(HCl)

Mp=161-163° C.; ¹H NMR (DMSO) 10.65 (brs, 1H), 7.27 (d, 2H, J=8.8 Hz),7.17 (d, 1H, J=8.8 Hz), 7.03 (d, 2H J=8.6 Hz), 6.99 (d, 1H, J=2.5 Hz),6.82-6.77 (m, 4H), 6.71 (dd, 1H, J=8.8 Hz, J=2.5 Hz), 5.17 (s, 2H), 4.27(m, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.44-3.30 (m, 4H), 3.17 (m, 2H),2.16 (s, 3H), 1.82-1.77 (m, 4H), 1.63-1.48 (m, 4H); MS eI m/z 499 (M+);CHN calc for C₃₂H₃₈N₂O₃+1HCl.

EXAMPLE NO. 922-(4-Ethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol

Mp=173-175° C.; ¹H NMR (DMSO) 8.69 (s, 1H), 7.25 (d, 2H, J=8.8 Hz), 7.04(d, 1H, J=8.8 Hz), 6.99 (dd, 2H, J=6.8 Hz, J=2.0 Hz), 6.80 (d, 1H, J=2.2Hz), 6.73 (s, 4H), 6.59 (dd, 1H, J=8.5 J=2.2), 5.09 (s, 2H), 4.05 (q,2H, J=7.03 Hz), 3.93 (t, 2H, J=6.0 Hz), 2.62-2.56 (m, 2H), 2.41-2.36 (m,4H), 2.09 (s, 3H), 1.45-1.41 (m, 4H), 1.38-1.30 (m, 5H); MS eI m/z 484(M+); CHN calc for C₃₁H₃₆N₂O₃+0.25H₂O.

EXAMPLE NO. 931-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-ethoxy-phenyl)-3-methyl-1H-indol-5-ol

Mp=133-135° C.; ¹H NMR (DMSO) 8.69 (s, 1H), 7.25 (d, 2H, J=8.8 Hz), 7.04(d, 1H, J=8.8 Hz), 6.99 (dd, 2H, J=6.8 Hz, J=2.0 Hz), 6.80 (d, 1H, J=2.2Hz), 6.73 (s, 4H), 6.59 (dd, 1H, J=8.5 Hz, J=2.2 Hz), 5.09 (s, 2H), 4.05(q, 2H, J=7.03 Hz), 3.90 (t, 2H, J=6.1 Hz), 2.75 (t, 2H, J=6.0 Hz),2.62-2.58 (m, 4H), 2.09 (s, 3H),1.58-1.44 (m, 8H), 1.33 (t, 3H, J=7.0Hz); IR (KBr) 2930, 1470, 1250 CM-1; MS eI m/z 498 (M+); CHN calc forC₃₂H₃₈N₂O₃.

EXAMPLE NO. 944-{5-Fluoro-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl}-phenol(HCl)

Mp=223-225° C.; ¹H NMR (DMSO) 10.30 (br s, 1H), 7.27-7.23 (m, 2H), 7.17(d, 2H, J=8.6 Hz), 6.88-6.79 (m, 7H), 5.20 (s, 2H), 4.28 (t, 2H, J=5.0Hz), 3.42-3.35 (m, 4H), 3.00-2.85 (m, 2H), 2.14 (s, 3H), 1.78-1.70 (m,4H), 1.67-1.59 (m, 1H), 1.40-1.26 (m, 1H); MS eI m/z 458 (M+).

EXAMPLE NO. 951-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-3-methyl-2-phenyl-1H-indol-5-ol(HCl)

Mp=203-204° C.; ¹H NMR (DMSO) 10.50 (brs, 1H), 8.80 (s, 1H), 7.50-7.38(m, 5H); 7.10 (d, 1H, J=8.8 Hz), 6.83-6.77 (m, 5H), 6.60 (d, 1H, J=6.6Hz), 5.15 (s, 2H), 4.26 (t, 2H, J=5.2 Hz), 3.45-3.35 (m, 4H), 3.21-3.10(m, 2H), 2.12 (s, 3H), 1.85-1.75 (m, 4H), 1.70-1.51 (m, 4H); MS eI m/z454 (M+); CHN calc for C₃₀H₃₄N₂O₂+1HCl.

EXAMPLE NO. 962-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-pyrollidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol

Mp=105-110° C.; CHN calc'd for C₂₈H₃₀N₂O₃+0.4H₂O; ¹H NMR (DMSO) 9.65 (s,1H), 8.67 (s, 1H), 7.15 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=8.6 Hz), 6.84(d, 2H, J=2H), 6.79 (d, 1H, J=2.4 Hz), 6.56 (dd, 1H, J=8.6, 2.2 Hz),6.74 (s, 4H), 5.09 (s, 2H), 3.95 (t, 2H, J=5.7 Hz), 3.39-3.23 (m, 4H),2.80-2.75 (m, 2H), 2.09 (s, 3H), 1.67-1.64 (m, 4H); IR (KBr) 3410 (br),1620, 1510 cm⁻¹; MS (EI) m/z 442

EXAMPLE NO. 981-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol(HCl)

Mp=168-171° C.; ¹H NMR (DMSO) 10.11 (br s, 1H), 9.70 (s, 1H), 8.71 (s,1H); 7.15 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=8.8 Hz), 6.85 (d, 2H, J=8.8Hz), 6.80-6.77 (m, 5H), 6.56 (dd, 1H, J=8.8 Hz, 2.2 Hz), 5.11 (s, 2H),4.26 (t, 2H, J=4.6 Hz), 3.48-3.30 (m, 4H), 3.22-3.08 (m, 2H), 2.09 (s,3H), 1.83-1.76 (m, 4H), 1.67-1.48 (m, 4H); IR (KBr) 3500 br, 3250 br,2900, 1610; MS FAB m/z 471 (M+H+); CHN calcd for C₃₀H₃₄N₂O₃+2.5H₂O+HCl.

EXAMPLE NO. 98 Acetate Salt

Made by the precipitation of No. 98 free base from acetone and aceticacid.

Mp=174-178° C.

EXAMPLE NO. 991-[4-(2-Azocan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol

Mp=98-102° C.; ¹H NMR (DMSO) 9.63 (s, 1H), 8.68 (s, 1H), 7.15-7.13 (m,2H), 7.05 (d, 1H, J=8.5 Hz), 6.83 (dd, 2H, J=2.0 Hz, 6.6 Hz), 6.79 (d,1H, J=2.2 Hz), 6.73 (s, 4H), 6.55 (dd, 1H, J=2.2 Hz, 8.6 Hz), 5.08 (s,2H), 3.89 (t, 2H, J=5.7 Hz), 2.74 (t, 2H, J=5.4 Hz), 2.55 (bs, 4H), 2.08(s, 3H), 1.55 (s, 2H), 1.46 (s, 8H); IR 3400, 2900, 1250 cm⁻¹; MS eI m/z484 (M+); CHN calcd for C₃₁H₃₆N₂O₃+0.30H₂O.

EXAMPLE NO. 1002-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-dimethyl-1-yl-ethoxy)-benzyl]-1H-indol-5-ol

Mp=95-105° C.; IR (KBr) 3400 br, 2900, 1610 cm⁻¹; MS eI m/z 416 (M+);CHN calcd for C₂₆H₂₈N₂O₃+0.5H₂O.

EXAMPLE NO. 1012-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-diethyl-1-yl-ethoxy)-benzyl]-1H-indol-5-ol

Mp=100-107° C.; CHN calc'd for C₂₈H₃₂N₂O₃+0.25H₂O; ¹H NMR (DMSO) 9.64(s, 1H), 8.67 (s, 1H), 7.14 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=8.8 Hz),6.84 (d, 2H, J=8.6 Hz), 6.79 (d, 1H, 2.2 Hz), 6.74 (s, 4H), 6.56 (dd,1H, J=8.8, 2.4 Hz), 5.09 (s, 2H), 3.95-3.85 (m, 2H), 2.80-2.60 (m, 2H),2.58-2.40 (m, 4H), 2.09 (s, 3H), 0.93 (t, 6H, J=7.0 Hz); IR (KBr) 3410(br), 2950, 1610, 1510 cm⁻¹; MS FAB 445 (M+H+).

EXAMPLE NO. 1021-[4-(2-Dipropylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol

Mp=83-86° C.; ¹H NMR (DMSO) 9.64 (s, 1H), 8.67 (s, 1H), 7.14 (d, 2H,J=8.6), 7.04 (d, 1H, J=8.6 Hz), 6.83 (d, 2H, J=8.6 Hz), 6.78 (d, 1H,J=2.2 Hz), 6.72 (m, 4H), 6.55 (dd, 1H, J=2.4 Hz, 8.2 Hz), 5.08 (s, 2H),3.88 (t, 2H, J=6.0 Hz), 2.80-2.63 (m, 2H), 2.59-2.45 (m, 4H), 2.10 (s,3H), 1.41-1.30 (m, 4H), 0.79 (t, 6H, J=7.3 Hz); IR 3400, 2900, 1250; MSFAB m/z 473 [M+H+]; CHN calcd for C₃₀H₃₆N₂O₃+0.20H₂O.

EXAMPLE NO. 1031-[4-(2-Dibutylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol

Foam; ¹H NMR (DMSO) 9.63 (s, 1H), 8.66 (s, 1H), 7.15 (d, 2H, J=8.6 Hz),7.05 (d, 1H, J=8.8 Hz), 6.83 (d, 2H, J=8.6 Hz), 6.79 (d, 1H, J=4.2 Hz),6.78-6.71 (m, 4H), 6.55 (dd, 1H, J=8.6 Hz J=2.4 Hz), 5.10 (s, 2H), 3.88(t, 2H, J=5.5 Hz), 2.68-2.62 (m, 2H), 2.42-2.34 (m, 4H), 2.08 (s, 3H),1.38-1.19 (m, 8H), 0.82 (t, 6H, J=7.2 Hz); IR (KBr) 3400, 1450 cm−1; MSeI m/z 501 (M+).

EXAMPLE NO. 1041-[4-(2-Diisopropylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol

Mp=96-102° C.; ¹H NMR (DMSO) 9.64 (s, 1H), 8.67 (s, 1H), 7.14 (d, 2H,J=8.6 Hz), 7.04 (d, 1H, J=8.6 Hz), 6.83 (d, 2H, J=8.6 Hz), 6.79 (d, 1H,J=2.4 Hz), 6.77-6.69 (m, 4H), 6.56 (dd, 1H, J=8.6 Hz, 2.2 Hz), 5.08 (s,2H), 3.75 (t, 2H, J=7.0 Hz), 3.01-2.92 (m, 2H), 2.67 (t, 2H, J=7.0 Hz),2.09 (s, 3H), 0.93 (d, 12H, 6.6 Hz); IR (KBr) 3400 br, 2940, 1620 cm⁻¹;MS FAB m/z 473 (M+H+); CHN calcd for C₃₀H₃₆N₂O₃+0.5H₂O.

EXAMPLE NO. 1051-{4-[2-(Butyl-methyl-amino)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol

Mp=102-107° C.; ¹H NMR (DMSO) 9.60 (s, 1H), 8.67 (s, 1H),7.14 (d, 2H,J=8.4 Hz), 7.04 (d, 1H, J=8.6 Hz), 6.82 (d, 2H, J=8.8 Hz), 6.78 (d, 1H,J=2.3 Hz), 6.73 (s, 4H), 6.55 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 5.08 (s,2H), 3.92 (t, 2H, J=6.0 Hz), 2.64-2.59 (m, 2H), 2.38-2.29(m, 2H), 2.20(br s, 3H), 2.08 (s, 3H), 1.40-1.31 (m 2H), 1.25-1.19 (m, 2H), 0.83 (t,3H, 7.2 Hz); IR (KBr) 3420, 1460, 1230 cm⁻¹; MS eI m/z 638 (M+).

EXAMPLE NO. 1082-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol

Mp=121-123° C.; ¹H NMR (DMSO) 9.65 (s, 1H), 8.68 (s, 1H), 7.14 (d, 2H,J=8.6 Hz), 7.04 (d, 1H, J=8.8 Hz), 6.84 (d, 2H, J=8.6 Hz), 6.79 (d, 1H,J=2.0 Hz), 6.74 (s, 4H), 6.56 (dd, 1H, J=8.8 Hz, 2.4 Hz), 5.09 (s, 2H),3.97-3.86 (m, 2H), 2.95-2.73 (m, 2H), 2.62-2.53 (m, 1H), 2.36-2.14 (m,2H), 2.09 (s, 3H), 1.61-1.30 (m, 4H), 1.28-1.09 (m, 2H), 0.98 (d, 3H,J=5.1 Hz); IR (KBr) 3400, 2920, 2850, 1610 cm⁻¹; CHN calcd forC₃₀H₃₄N₂O₃+0.25H₂O.

EXAMPLE NO. 1092-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(3-methyl-piperdin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol

Mp=121-123° C.; ¹H NMR (DMSO) 9.64 (s, 1H), 8.67 (s, 1H), 7.14 (dd, 2H,J=8.3 Hz, 1.4 Hz), 7.04 (dd, 1H, J=8.6 Hz, 1.2 Hz), 6.84 (dd, 2H, J=8.6Hz, 1.7 Hz), 6.79 (s, 1H), 6.79 (s, 4H), 6.56 (d, 1H, J=8.6 Hz), 5.08(s, 2H), 3.94 (t, 2H, J=5.0 Hz), 2.86-2.71 (m, 2H), 2.63-2.50 (m, 2H),2.48 (s, 3H), 1.92-1.79 (m, 2H), 1.63-1.35 (m, 5H), 0.79 (d, 3H, J=5.2Hz); IR (KBr) 3400, 2910, 1625 cm⁻¹; CHN calcd for C₃₀H₃₄N₂O₃+0.25H₂O.

EXAMPLE NO. 1102-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol(HCl)

Mp=154-162° C.; ¹H NMR (DMSO) 10.00 (brs, 1H), 9.71 (s, 1H), 8.71 (s,1H), 7.15 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=8.6 Hz), 6.85 (d, 2H, J=8.6Hz), 6.83-6.77 (m, 4H), 6.57 (dd, 1H, J=8.6 Hz, 2.2 Hz), 5.11 (s, 2H),4.27 (t, 2H, J=4.8 Hz), 3.51-3.35 (m, 4H), 3.01-2.87 (m, 2H), 2.09 (s,3H), 1.74 (d, 2H, J=13.4 Hz), 1.61-1.37 (m, 4H), 0.88 (d, 3H, J=6.4 Hz);IR (KBr) 3410, 2910, 1620 cm⁻¹; MS eI m/z 470 (M+H+); CHN calcd forC₃₀H₃₄N₂O₃+HCl+2H₂O.

EXAMPLE NO. 1111-{4-[2-(3,3-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol

Mp=100° C.; ¹H NMR (DMSO) 9.65 (s, 1H), 8.67 (s, 1H), 7.15 (d, 2H, J=8.6Hz), 7.05 (d, 1H, J=8.8 Hz), 6.84 (d, 2H, J=8.6 Hz), 6.79 (d, 1H, J=2.4Hz), 6.74 (s, 4H), 6.56 (dd, 1H, J=8.8, 2.4 Hz), 5.09 (s, 2H), 3.93 (t,2H, J=5.7 Hz), 2.60-2.50 (m, 2H), 2.37-2.25 (m, 2H), 2.09 (s, 3H),2.10-1.99 (m, 2H), 1.46 (t, 2H, J=5.9 Hz), 1.13 (t, 2H, J=6.4 Hz), 0.86(s, 6H); MS eI m/z 484.

EXAMPLE NO. 1121-{4-[2-((cis)-2,6-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol

Mp=114-121° C.; ¹H NMR (DMSO) 9.62 (s, 1H), 8.64 (s, 1H), 7.11 (d, 2H,J=8.6 Hz), 7.01 (d, 1H, J=8.6 Hz), 6.81 (d, 2H, J=8.8 Hz), 6.76 (d, 1H,J=2.2 Hz), 6.72-6.66 (m, 4H), 6.53 (dd, 1H, J=8.6 Hz, 2.2 Hz), 5.06 (s,2H), 3.86-3.72 (m, 2H), 2.86-2.76 (m, 2H), 2.43-2.35 (m, 2H), 2.06 (s,3H), 1.78-1.59 (m, 3H), 1.29-1.17 (m, 1H), 1.12-0.92 (m, 8H); IR (KBr)3400 br, 2920, 1630 cm−1; MS FAB m/z 485 (M+H+); CHN calcd forC₃₁H₃₆N₂O₃+0.1 acetone+0.75H₂O.

EXAMPLE NO. 1132-(4-Hydroxy-phenyl)-1-{4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-benzyl}-3-methyl-1H-indol-5-ol

Mp=80-90° C.; ¹H NMR (DMSO) 9.66 (s, 1H), 8.68 (s, 1H), 7.15 (d, 2H,J=7.6 Hz), 7.04 (d, 1H, J=8.8 Hz), 6.84 (dd, 2H, J=2.0 Hz, 6.6 Hz), 6.78(d, 1H, 2.2 Hz), 6.73 (s, 4H), 6.55 (dd, 1H, J=2.2 Hz, 8.6 Hz), 5.09 (s,2H), 4.50 (d, 1H, J=4.2 Hz), 3.92 (t, 2H, J=5.8 Hz), 3.40 (m, 2H), 2.72(m, 2H), 2.60 (m, 2H), 2.10 (s, 3H), 2.15-2.05 (m, 1H), 1.75-1.63 (m,2H), 1.42-1.28 (m, 2H); IR (KBr) 3400, 2900, 1250 cm⁻¹; MS eI m/z 472(M+); CHN calcd for C₂₉H₃₂N₂O₄+0.11CH₂Cl₂.

EXAMPLE NO. 114 (1S,4R)-1-{4-[2-(2-Aza-bicyclo [2.2.1]hept-2-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol

Mp=125-130° C.; ¹H NMR (DMSO) 9.65 (s, 1H), 8.67 (s, 1H), 7.13 (d, 2H,J=8.6 Hz), 7.04 (d, 1H, J=8.5 Hz), 6.83 (dd, 2H, J=2.0 Hz, 6.6 Hz), 6.78(d, 1H, J=2.2 Hz), 6.73 (s, 4H), 6.55 (dd, 1H, J=2.2 Hz, 8.6 Hz), 5.08(s, 2H), 3.95-3.8 (m, 2H), 2.90-2.70 (3H), 2.30-2.20 (m, 2H), 2.10 (s,3H), 1.70-1.60 (m, 1H), 1.60-1.30 (m, 4H), 1.25-1.15 (m, 2H); IR (KBr)3400, 2950, 1500; MS (+) FAB m/z 469 [M+H]⁺; CHN calcd forC₃₀H₃₂N₂O₃+0.34 EtOAc.

EXAMPLE NO. 1152-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-ethoxy]-benzyl}-1H-indol-5-ol

Mp=98-100° C.; ¹H NMR (DMSO) 9.64 (s, 1H), 8.67 (s, 1H), 7.14 (d, 2H,J=8.6 Hz), 7.05 (d, 1H, J=8.6 Hz), 6.84 (d, 2H, J=8.6 Hz), 6.79 (d, 1H,J=2.4 Hz), 6.75-6.69 (m, 4H), 6.56 (dd, 1H, J=8.6 Hz, 2.4 Hz), 5.08 (s,2H), 3.83 (t, 2H, J=5.9 Hz), 3.12-3.07 (m, 1H), 2.94-2.87 (m, 1H), 2.85(d, 1H, J=9.2 Hz), 2.78-2.70 (m, 1H), 2.17 (d, 1H, J=9.2 Hz), 2.09 (s,3H), 1.55-1.42 (m, 2H), 1.29 (q, 2H, J=13.6 Hz), 1.14 (s, 3H), 1.11-1.02(m, 2H), 0.96 (s, 3H), 0.82 (s, 3H); IR (KBr) 3400 br, 2940, 2900, 1630cm⁻¹; MS ESI m/z 525 (M+H⁺); CHN calcd for C₃₄H₄₀N₂O₃+0.5H₂O.

EXAMPLE NO. 1162-(4-Fluoro-phenyl)-3-methyl-1-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-1H-indol-5-ol(HCl)

Mp=201-203° C.; ¹H NMR (DMSO) 10.22 (s, 1H), 8.78 (s, 1H), 7.45-7.35 (m,2H), 7.34-7.25 (m, 2H), 7.11 (d, 1H, J=8.6 Hz), 6.90-6.70 (m, 5H), 6.61(dd, 1H, J=2.4 Hz, 8.8 Hz), 5.15 (s, 2H), 4.27 (t, 2H, 4.8 Hz),3.50-3.34 (m, 4H), 3.0-2.85 (m, 2H), 2.10 (s, 3H), 1.80 (m, 5H),1.40-1.25 (m, 1H); MS eI m/z 458 (M+); CHN calcd for C₂₉H₃₁FN₂O₂+1HCl.

EXAMPLE NO. 1171-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-fluoro-phenyl)-3-methyl-1H-indol-5-ol

Mp=181-184° C.; ¹H NMR (DMSO) 10.68 (s, 1H), 8.80 (s, 1H), 7.50-7.36 (m,2H), 7.34-7.26 (m, 2H), 7.12 (d, 1H, J=8.8 Hz), 6.86-6.73 (m, 5H), 6.63(dd, 1H, J=2.2 Hz, 8.5 Hz), 5.13 (s, 2H), 4.29 (t, 2H, J=5.2 Hz),3.50-3.30 (m, 4H), 3.20-3.08 (m, 2H), 2.11 (s, 3H), 1.90-1.70 (m, 4H),1.68-1.45 (m, 4H); IR (KBr) 3500, 3100, 2910, 1450, 1250 cm⁻¹; MS eI m/z472 (M+); CHN calcd for C₃₀H₃₃FN₂O₂+1 HCl.

EXAMPLE NO. 1182-(3-Methoxy-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol(HCl)

Mp=161-163° C.; ¹H NMR (DMSO) 10.12 (brs, 1H), 9.25 (s, 1H), 8.71 (s,1H), 7.05 (d, 1H, J=8.5 Hz), 6.85-6.79 (m, 8H), 6.57 (dd, 1H, J=8.5 Hz,J=2.2 Hz), 5.13 (s, 2H), 4.27 (t, 2H, J=5.0 Hz), 3.64 (s, 3H), 3.44-3.37(m, 4H), 2.93-2.85 (m, 2H), 2.11 (s, 3H), 1.80-1.60 (m, 5H), 1.40-1.25(m, 1H); MS eI m/z 486 (M+); CHN calc for C₃₀H₃₄N₂O₄+1HCl+1H₂O; IR (KBr)3190, 1470, 1230 cm⁻¹.

EXAMPLE NO. 1192-Benzo[1,3]dioxol-5-yl-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol(HCl)

Mp=122-125° C.; ¹H NMR (DMSO) 9.80 (brs, 1H), 8.73 (s, 1H), 7.07 (d, 1H,J=8.7 Hz), 7.02 (d, 1H, J=8.0 Hz), 6.89 (d, 1H,J=1.7 Hz), 6.80-6.75 (m,6H), 6.58 (dd, 1H, J=6.4 Hz, J=2.2 Hz), 6.06 (s, 2H), 5.13 (s, 2H),4.30-4.19 (m, 2H), 3.51-3.30 (m, 4H), 2.99-2.85 (m, 2H), 2.10 (s, 3H),1.81-1.59 (m, 5H), 1.41-1.26 (m, 1H); MS eI m/z 484(M+); CHN calc forC₃₀H₃₂N₂O₄+HCl+0.26H₂O.

EXAMPLE NO. 1202-(4-Isopropoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol(HCl)

Mp=120-125° C.; ¹H NMR (DMSO) 10.18 (s, 1H), 8.73 (s, 1H), 7.25 (d, 2H,J=8.6 Hz), 7.04 (d, 1H, J=8.8 Hz), 6.99 (d, 2H, J=8.8 Hz), 6.82-6.80 (m,5H), 6.59 (dd, 1H, J=2.2 Hz, 8.6 Hz), 5.12 (s, 2H), 4.67-4.61 (m, 1H),4.27 (t, 2H, J=4.8 Hz), 3.50-3.35 (m, 4H), 3.0-2.85 (m, 2H), 2.10 (s,3H), 1.80-1.60 (m, 5H), 1.40-1.25 (m, 7H); IR (KBr) 3400, 3000, 1500,1250; MS eI m/z 498 (M+); CHN calcd for C₃₂H₃₈N₂O₃+1.0HCl+0.70H₂O.

EXAMPLE NO. 1211-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-isopropoxy-phenyl)-3-methyl-1H-indol-5-ol(HCl)

Mp=120-125° C.; ¹H NMR (DMSO) 10.36 (s, 1H), 8.73 (s, 1H), 7.26-7.23 (m,2H), 7.05 (d, 1H, J=8.8 Hz), 7.01-6.98 (m, 2H), 6.85-6.75 (m, 5H), 6.57(dd, 1H, J=2.2 Hz, 8.6 Hz), 5.12 (s, 2H), 4.67-4.61 (m, 1H), 4.27 (t,2H, J=4.8 Hz), 3.50-3.30 (m, 4H), 3.20-3.10 (m, 2H), 2.10 (s, 3H),1.85-1.75 (m, 4H), 1.65-1.50 (m, 4H), 1.27 (d, 6H, J=6.1 Hz); IR (KBr)3400, 1500, 1250: MS eI m/z 512 (M+); Calcd forC₃₃H₄₀N₂O₃+1.0HCl+0.5H₂O.

EXAMPLE NO. 1222-(4-Cyclopenyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol

Mp=121-135° C.; ¹H NMR (DMSO) 9.80 (br s, 1H), 8.72 (s, 1H), 7.24 (d,2H, J=8.8 Hz), 7.05 (d, 1H, J=8.8 Hz), 6.98 (d, 2H, J=8.8 Hz), 6.83-6.78(m, 5H), 6.57 (dd, 1H, J=8.8 Hz, 2.4 Hz), 5.13 (s, 2H), 4.86-4.82 (m,1H), 4.25 (t, 2H, J=4.8 Hz), 3.50-3.38 (m, 4H), 2.92 (q, 2H, J=8.8 Hz),2.11 (s, 3H), 1.98-1.85 (m, 2H), 1.81-1.56 (m, 11H), 1.41-1.29 (m, 1H);IR (KBr) 3400, 2920, 1620 cm−1; MS eI m/z 524 (M+); CHN calcd forC₃₄H₄₀N₂O₃+0.5H₂O.

EXAMPLE NO. 1233-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethyl-phenyl)-1H-indol-5-ol

Mp=174° C.; ¹H NMR (DMSO) 8.8 (s, 1H), 7.82 (d, 2H, J=8.1 Hz), 7.59 (d,2H, J=7.9 Hz), 7.17 (d, 1H, J=8.6 Hz), 6.86 (d, 1H, J=2.4 Hz), 6.75-6.68(m, 4H), 6.65 (dd, 1H, J=8.8 Hz, 2.4 Hz), 5.16 (s, 2H), 3.93 (t, 2H,J=5.7 Hz), 2.62-2.56 (m, 2H), 2.42-2.32 (m, 4H), 2.15 (s, 3H), 1.48-1.40(m, 4H), 1.39-1.29 (m, 2H); IR (KBr) 3410, 2910, 2850, 1620 cm−1; MS eIm/z 508 (M+); CHN calcd for C₃₀H₃₁F₃N₂O₂+0.25H₂O.

EXAMPLE NO. 1243-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-p-tolyl-1H-indol-5-ol

Mp=162-164° C.; ¹H NMR (DMSO) 8.70 (s, 1H), 7.28-7.24 (m, 4H), 7.07 (d,1H, J=8.4 Hz), 6.81 (d, 1H, J=2.2 Hz), 6.73 (s, 4H), 6.58 (dd, 1H, J=2.4Hz, 8.8 Hz), 5.11 (s, 2H), 3.92 (t, 2H, J=5.9 Hz), 2.55 (t, 2H, J=5.9Hz), 2.45-2.30 (m, 7H), 2.10 (s, 3H), 1.50-1.40 (m, 4H), 1.48-1.35 (m,2H); IR (KBr) 3400, 2900, 1200; MS eI m/z 454 (M+); CHN calcd forC₃₀H₃₄N₂O₂.

EXAMPLE NO. 1252-(4-Chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol(HCl)

Mp=161-164° C.; ¹H NMR (DMSO) 10.12 (brs, 1H), 8.80 (s, 1H), 7.53 (d 2H,J=8.3 Hz), 7.36 (d, 2H, J=8.8 Hz), 7.12 (d, 1H, J=8.8 Hz), 6.85-6.75 (m,5H), 6.63 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 5.14 (s, 2H), 4.29-4.22 (m, 2H),3.45-3.36 (m, 4H), 2.97-2.84 (m, 2H), 2.11 (s, 3H), 1.83-1.61 (m, 5H),1.37-1.25 (m, 1H); MS eI m/z 475 (M+); CHN calc forC₂₉H₃₁ClN₂O₂+HCl+0.25H₂O.

EXAMPLE NO. 1262-(2,4-Dimethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol

Mp=85-92° C.; ¹H NMR (DMSO) 8.62 (s, 1H), 7.10 (d, 1H, J=8.4 Hz), 7.01(d, 1H, J=8.6 Hz), 6.80-6.70 (m, 5H), 6.69 (d, 1H, 2.2 Hz), 6.59 (dd,1H, J=2.4 Hz, 8.5 Hz), 6.52 (dd, 1H, J=2.4 Hz, 8.8 Hz), 5.02 (d, 1H,J=6.5 Hz), 4.83 (d, 1H, J=6.3 Hz), 4.0-3.90 (m, 2H), 3.80 (s, 3H), 3.67(s, 3H), 2.65-2.50 (m, 2H), 2.45-2.30 (m, 4H), 2.0 (s, 3H), 1.55-1.40(m, 4H), 1.39-1.30 (m, 2H); IR (KBr) 3400, 2900, 1520, 1250; MS eI m/z500 (M+); CHN calcd for C₃₁H₃₆N₂O₄+0.05CH₂Cl₂.

EXAMPLE NO. 1272-(3-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol

Mp=115-118° C.; ¹H NMR (DMSO) 9.57 (s, 1H), 8.71 (s, 1H), 7.27-7.23 (t,1H, J=8.1 Hz), 7.06-7.04 (d, 1H, J=8.8 Hz), 6.81-6.74 (m, 8H), 6.59-6.56(dd, 1H, J=2.3 Hz, J=6.3 Hz), 5.12 (s, 2H), 3.94-3.91 (t, 2H, J=5.9 Hz),2.57-2.54 (t, 2H, J=5.8 Hz), 2.36 (s, 4H), 2.11 (s, 3H), 1.45-1.41 (m,4H), 1.34-1.33 (m, 2H); IR (KBr) 3400, 2900 cm⁻¹; MS eI m/z 456 (M+);CHN calcd for C₂₉H₃₂N₂O₃+1.0H₂O.

EXAMPLE NO. 1281-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(3-hydroxy-phenyl)-3-methyl-1H-indole-5-ol

Mp=94-97° C.; ¹H NMR (DMSO) 9.58 (s, 1H), 8.71 (s, 1H), 7.27-7.23 (t,1H, J=7.9 Hz), 7.07-7.04 (d, 1H, J=8.7 Hz), 6.81-6.74 (m, 8H), 6.59-6.56(dd, 1H, J=2.4 Hz, J=6.3 Hz), 5.12 (s, 2H), 3.9 (m, 2H), 2.80 (s, 2H),2.65 (s, 4H), 2.11 (s, 3H), 1.54-1.50 (m, 8H); IR 3400, 2900 cm⁻¹; MS eIm/z 470 (M+); CHN calcd for C₃₀H₃₄N₂O₃+0.75H₂O+0.23 Ethyl Acetate.

EXAMPLE NO. 1292-(3-Fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol

Mp=117-119° C.; ¹H NMR (DMSO) 10.1 (s, 1H), 8.71 (s, 1H), 7.10-6.95 (m,4H), 6.80 (d, 1H, J=2.2 Hz), 6.74 (s, 4H), 6.59 (dd, 1H, J=2.2 Hz, 8.5Hz), 5.1 (s, 2H), 3.93 (t, 2H, J=5.9 Hz), 2.56 (t, 2H, J=5.8 Hz),2.44-2.30 (m, 4H), 2.10 (s, 3H), 1.45-1.40 (m, 4H), 1.36-1.32 (m, 2H);MS eI m/z 475 (M+); CHN calcd for C₂₉H₃₁FN₂O₃.

EXAMPLE NO. 1302-(3-Fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(azepan-1-yl-ethoxy)-benzyl]-1H-indol-5-ol

Mp=88-91° C.; ¹H NMR (DMSO) 10.10 (s, 1H), 8.71 (s, 1H), 7.12-6.94 (m,4H), 6.80(d, 1H, J=2.2 Hz), 6.74 (s, 4H), 6.58 (dd, 1H, J=2.2 Hz, 8.5Hz), 5.10 (s, 2H), 3.91(t, 2 H, J=5.9 Hz), 2.76 (t, 2H, J=5.9),2.62-2.60 (m, 4H), 2.10 (s, 3H), 1.70-1.40 (m, 8H); MS eI m/z 488 (M+);CHN calcd for C₃₀H₃₃FN₂O₃.

EXAMPLE NO. 1312-(3-Methoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole-5-ol

Mp=120-123° C.; ¹H NMR (DMSO) 8.76 (s, 1H), 7.42-7.46 (t, 1H, J=7.9 Hz),7.12-7.09 (d, 1H, J=8.7 Hz), 6.99-6.92 (m, 2H), 6.86-6.83 (m, 2H), 6.76(s, 4H), 6.63-6.60 (dd, 1H, J=2.1 Hz, J=6.5 Hz), 5.14 (s, 2H),3.96-3.92(t, 2H, J=5.9 Hz), 3.70 (s, 3H), 2.59-2.55 (t, 2H, J=5.9 Hz),2.37 (s, 4H), 2.14 (s, 3H), 1.49-1.44 (m, 4H), 1.35-1.34 (m, 2H); IR3400, 2950, 1600 cm⁻¹; MS eI m/z 471 (M+); CHN calcd for C₃₀H₃₄N₂O₃.

EXAMPLE NO. 1323-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethoxy-phenyl)-1H-indole-5-ol

Mp=122-125° C.; ¹H NMR (DMSO) 8.80 (s, 1H), 7.51-7.45 (m, 4H), 7.17-7.14(d, 1H, J=8.7 Hz), 6.85-6.84 (d, 1H, J=2.0 Hz), 6.75-6.69 (m, 4H),6.66-6.62 (m, 1H), 5.14 (s, 2H), 3.95-3.92 (t, 2H, J=5.8 Hz), 2.59-2.55(t, 2H, J=5.6 Hz), 2.49-2.38 (m, 4H), 2.13 (s, 3H), 1.47-1.44 (m, 4H),1.36-1.34 (d, 2H, J=4.8 Hz); IR 3400, 2900, 1600 cm⁻¹; MS eI m/z 525(M+); CHN calcd for C₃₀H₃₁F₃N₂O₃+0.25H₂O.

Synthetic Procedures and Physical Data for Compounds Substituted withChloro, Ethyl or Cyano Groups at the 3-Position of the Indole

TABLE 8

Example No. X Q Z No. 133 Cl H

No. 134 Cl H

No. 135 Cl H

No. 136 Cl CH₃

No. 137 Et H

No. 138 CN H

No. 139 CN H

Synthesis of 3-Chloro Analogues No. 133-No. 136

EXAMPLE NO. 140 Formation of Hydrazone

4-Benzyloxyphenylhydrazine CAS No. [51145-58-5] (50.0 g, 233.4 mmol) wasmixed with 4-benzyloxyacetophenone CAS No. [54696-05-8] (63.0 g, 280.0mmol) in pure ethanol (800 mL). A catalytic amount of acetic acid (5drops) was added. The reaction was heated to reflux for 2.5 hrs. Duringthe course of refluxing, the condensed product solidified out of the hotsolution. The reaction was cooled down to rt. The desired product wascollected by vacuum filtration as a light yellow solid (85 g, 86%).Mp=165-174° C.; ¹H NMR (DMSO) 8.91 (s, 1H), 7.68 (d, 2H, J=8.8 Hz),7.48-7.32 (m, 10H), 7.12 (d, 2H, J=9 Hz), 7.00 (d, 2H, J=8.8 Hz), 6.88(d, 2H, J=9.0 Hz). 5.11 (s, 2H), 5.01 (s, 2H), 2.17 (s, 3H); MS eI m/z422 (M+).

EXAMPLE NO. 141 Formation of Indole from Hydrazone:5-Benzyloxy-2-(4-benzyloxy-phenyl)-1H-indole

A flask was charged withN-(4-Benzyloxy-phenyl)-N′-[1-(4-benzyloxy-phenyl)-ethylidene]-hydrazine(No. 140) (10.0 g, 23.7 mmol), ZnCl₂ (8.06 g, 59.17 mmol), acetic acid(70 mL). The reaction flask was heated to 105° C. for no more than 20min. During the heating period, the reaction was monitored carefully byTLC for the disappearance of the starting material. The progress of thereaction could be shown as the product solidified out of the solutionwhile heating. The reaction was then cooled to rt and more productcrashed out was observed. The reaction content was poured into aseparatory funnel containing ether (100 mL) and H₂O (200 mL), which wasshaken vigorously. The insoluble residue as the desired product stayedin the ether layer which was collected by vacuum filtration. The productwas further purified by trituration in ether to give a light gray solid(4.4 g, 46%)

Mp=202-204° C.; ¹H NMR (DMSO) 11.24 (s, 1H), 7.73 (d, 2H, J=8.8 Hz),7.48-7.41(m, 4H), 7.45-7.27 (m, 6H), 7.25 (d, 1H, J=8.6 Hz), 7.12-7.04(m, 3H), 6.77 (dd, 1H, J=2.4 Hz, 8.6 Hz), 6.65 (d, 1H, J=1.5 Hz), 5.14(s, 2H), 5.08 (s, 2H); IR 3420, 3000, 1625 cm⁻¹; MS eI m/z 405 (M+); CHNcalcd for C₂₈H₂₃NO₂+0.40H₂O.

EXAMPLE NO. 142 Chlorination of Indole to Render5-Benzyloxy-3-chloro-2-(4-benzyloxy-phenyl)-1H-indole

A flask was charged with 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1H-indoleNo. 141 (8.0 g, 20.0 mmole) and CH₂Cl₂ (50 ml). The reaction was cooledto 0° C. and n-chlorosuccinimide (2.9 g, 22 mmole) was added. Thereaction was stirred at 0° C. for 20 min. The reaction was then washedwith 10% sodium sulfite solution, dried over MgSO₄, and concentrated. Tothe resulting brown solid was added MeOH and the mixture was stirred for15 min. The solid was filtered to give 6.8 g of a tan solid (78%).

Mp=157-160° C.; ¹H NMR (DMSO) 11.5 (s, 1H), 7.80 (d, 2H, J=7.0 Hz),7.42-7.28 (m, 11H), 7.17 (d, 2H, J=8.7 Hz), 7.01 (d, 1H, J=2.2 Hz), 6.88(dd, 1H, J=8.8 Hz, J=2.4 Hz), 5.17 (s, 2H), 5.13 (s, 2H); MS eI m/z 439(M+).

EXAMPLE NO. 1435-Benzyloxy-3-chloro-2-(2-methyl-4-benzyloxy-phenyl)-1H-indole

This indole synthesized analogously to indole No. 142 immediatelypreceding: Mp=¹H NMR (DMSO) 11.34 (s, 1H), 7.48-7.44 (m, 4H), 7.42-7.24(m, 8H), 7.02 (dd, 2H, J=9.3 Hz, J=2.4 Hz), 6.95 (dd, 1H, J=8.4 Hz,J=2.6 Hz), 6.88 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 5.16 (s, 2H), 5.14 (s,2H), 2.23 (s, 3H); MS eI m/z 453 (M+).

EXAMPLE NO. 144 Alkylation of Indole to Give{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

This procedure was performed analogously to that outlined for thesynthesis of 3-methyl indole acetic acid ethyl esters outlined in method3. Mp=90-94° C.; ¹H NMR (DMSO) 7.45 (d, 4H, J=7.8 Hz),7.41-7.26 (m, 9H),7.14 (d, 2H, J=8.7 Hz), 7.04 (d, 1H, J=2.4 Hz), 6.91 (dd, 1H, J=9.0 Hz,J=2.5 Hz), 6.80-6.74 (m, 4H), 5.24 (s, 2H), 5.15 (s, 2H), 5.14 (s, 2H),4.66 (s, 2H), 4.12 (q, 2H, J=7.2 Hz), 1.16 (t, 3H, J=7.5 Hz); MS eI m/z631 (M+).

EXAMPLE NO. 145 Reduction of No. 144 to Render No. 1452-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-indol-1-ylmethyl]-phenoxy}-ethanol

This reaction was performed analogously to that outlined for thesynthesis of 3-methyl indoles outlined in method 4. Compound was notpurified or characterized, but used as obtained for the next step.

EXAMPLE NO. 146 Bromination of No. 145 to RenderBenzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-chloro-1H-indole

This reaction was performed analogously to that outlined for thesynthesis of 3-methyl indoles outlined in method 5. Mp=155-158° C.; ¹HNMR (DMSO) 7.45 (d, 4H, J=7.8 Hz),7.41-7.25 (m, 9H), 7.14 (d, 2H, J=8.7Hz), 7.04 (d, 1H, J=2.4 Hz), 6.91 (dd, 1H, J=9.0 Hz, J=2.5 Hz), 6.74 (s,4H), 5.24 (s, 2H), 5.15 (s, 2H), 5.14 (s, 2H), 4.20 (t, 2H, J=5.3 Hz),3.74 (t, 2H, J=5.3 Hz); MS eI m/z 651 (M+).

EXAMPLE NO. 147 Substitution of No. 146 with Piperidine to Render5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

This reaction performed analogously to that outlined for the synthesisof 3-methyl indoles outlined in method 6, using piperidine to substitutethe bromide.

Mp 96-98° C.; ¹H NMR (DMSO) 7.45 (d, 4H, J=7.8 Hz), 7.40-7.30 (m, 9H),7.14 (d, 2H, J=8.7 Hz), 7.04 (d, 1H, J=2.4 Hz), 6.91 (dd, 1H, J=9.0 Hz,J=2.5 Hz), 6.74 (s, 4H), 5.24 (s, 2H), 5.15 (s, 2H), 5.14 (s, 2H), 3.93(t, 2H, J=6.0 Hz), 2.56 (t, 2H, J=6.0 Hz), 2.41-2.32 (m, 4H), 1.48-1.39(m, 4H), 1.38-1.31 (m, 2H).

EXAMPLE NO. 1485-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole

Reaction performed the same as above except the substituting amine usedwas hexamethyleneamine.

Mp=94-97° C.; ¹H NMR (DMSO) 7.45 (d, 4H, J=7.8 Hz), 7.42-7.30 (m, 9H),7.14 (d, 2H J=8.7 Hz), 7.04 (d, 1H, J=2.4 Hz), 6.91 (dd, 1H, J=9.0 Hz,J=2.5 Hz), 6.74 (s, 4H), 5.24 (s, 2H), 5.15 (s, 2H), 5.14 (s, 2H), 3.93(t, 2H, J=6.0 Hz), 2.75 (t, 2H, J=6.0 Hz), 2.63-2.59 (m, 4H), 1.58-1.44(m, 8H); MS eI m/z 671 (M+).

EXAMPLE NO. 1495-Benzyloxy-2-(2-methyl-4-benzyloxy-phenyl)-3-chloro-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

Reactions to make this compound analogous to those used to make No. 147.

Oil; ¹H NMR(DMSO) 7.50-7.29 (m, 11H), 7.17 (d, 1H, J=8.4 Hz), 7.05 (d,1H, J=2.4 Hz), 7.02 (d, 1H, J=2.4 Hz), 6.93-6.85 (m, 2H), 6.75-6.65 (m,4H), 5.14 (s, 2H), 5.13 (s, 2H), 5.07 (m, 2H), 3.92 (t, 2H, J=5.9 Hz),2.55 (t, 2H, J=5.9 Hz), 2.42-2.29 (m, 4H), 1.94 (s, 3H), 1.44-1.40 (m,4H), 1.38-1.34 (m, 2H).

EXAMPLE NO. 1333-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol(Hcl)

Synthesized as described for example No. 134.

Mp=233-235° C.; ¹H NMR (DMSO) 10.50 (s, 1H), 9.88 (s, 1H), 9.01 (s, 1H),7.30-7.20 (m, 3H), 6.90-6.80 (m, 7H), 6.68 (dd, 1H, J=2.4, Hz, 8.8 Hz),5.20 (s, 2H), 4.22 (t, 2H, J=4.8 Hz), 3.47 (t, 2H, J=4.8 Hz), 3.10 (bm,4H), 1.90 (s, 4H); IR (KBr) 3400, 1625, 1475, 825 cm⁻¹; MS eI m/z 462(M+); CHN calcd for C₂₇H₂₇ClN₂O₃+1HCl+0.75H₂O.

EXAMPLE NO. 134 Removal of Benzyl Ethers to Render3-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol(HCl)

Benzyl ethers were removed analogously to that procedure outlined for3-methyl indoles outlined in method 7. This compound was then convertedto the hydrochloride salt as described previously in method 8;Mp=207-209° C.; ¹H NMR (DMSO) 10.10 (bs, 1H), 9.86 (s, 1H), 9.07 (s,1H), 7.26 (d, 2H, J=8.6 Hz), 7.22 (d, 1H, J=8.8 Hz), 6.87 (d, 2H, J=8.6Hz), 6.81-6.78 (m, 5H), 6.65 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 5.20 (s, 2H),4.27 (t, 2H, J=5.0 Hz), 3.44-3.37 (m, 4H), 3.00-2.85 (m, 2H), 1.81-1.60(m, 5H), 1.41-1.26 (m, 1H); IR (KBr) 3350, 1470, 1250 CM−1; MS eI m/z476 (M+); CHN calc for C₂₈H₂₉ClN₂O₃+HCl+1.5H₂O.

EXAMPLE NO. 1353-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indol-5-ol(HCl)

Synthesized as described for No. 134.

Mp=196-198° C.; ¹H NMR (DMSO) 10.10 (brs, 1H), 9.86 (s, 1H), 9.07 (s,1H), 7.26 (d, 2H, J=8.8 Hz), 7.22 (d, 1H, J=9.0 Hz), 6.87 (d, 2H, J=8.6Hz), 6.84-6.78 (m, 5H), 6.65 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 5.20 (s, 2H),4.27 (t, 2H, J=5.0 Hz), 3.45-3.30 (m, 4H), 3.21-3.10 (m, 2H), 1.82-1.76(m, 4H), 1.65-1.46 (m, 4H); MS eI m/z 491 (M+); CHN calc forC₂₉H₃₁ClN₂O₃+1HCl+0.37H₂O; IR (KBr) 3400, 3200, 1450, 1125

EXAMPLE NO. 1363-Chloro-2-(4-hydroxy-2-methyl-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol

Synthesized as described for No. 134 except the compound was notconverted into a salt.

Foam; ¹H NMR (DMSO) 9.64 (s, 1H), 9.01 (s, 1H), 7.25 (d, 1H, J=8.8 Hz),7.03 (d, 1H, J=8.1 Hz), 6.79 (d, 1H, J=2.4 Hz), 6.78-6.65 (m, 7H),5.06-4.92 (m, 2H), 3.94 (t, 2H, J=5.9 Hz), 2.62-2.57 (m, 2H), 2.42-2.32(m, 4H), 1.90 (s, 3H), 1.48-1.40 (m, 4H), 1.40-1.32 (m, 2H); MS eI m/z490 (M+); IR (KBr) 3430, 2900, 1450 cm⁻¹; CHN calc forC₂₉H₃₁ClN₂O₃+1.0H₂O.

Synthesis of 3-ethylindole Analogue No. 137

This compound was synthesized in exact analogy to the example given for3-methylindoles, supra, using methods a and 2-8. The only difference isthat the starting material used is 4′-(benzyloxy)-Butyrophenone CAS No.[26945-71-1] instead of 4′-(benzyloxy)-Propiophenone. Data forintermediates is as follows.

EXAMPLE NO. 150 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-ethyl-1H-indole

Mp=101-108° C.; MS eI m/z 433 (M+).

EXAMPLE NO. 151{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-ethyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Mp=72-75° C.; MS eI m/z 625 (M+).

EXAMPLE NO. 1522-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-ethyl-indol-1-ylmethyl]-phenoxy}-ethanol

Mp=105-113° C.; MS eI m/z 583 (M+).

EXAMPLE NO. 153Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-ethyl-1H-indole

Mp=140° C. (decomp.); MS eI m/z 647, 645 (M+, Br present).

EXAMPLE NO. 1545-Benzyloxy-2-(4-benzyloxy-phenyl)-3-ethyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

Mp=92-96° C.; ¹H NMR (DMSO) 7.47 (d, 4H, J=7.2 Hz), 7.42-7.39 (m, 4H),7.36-7.30 (m, 2H), 7.27 (d, 2H, J=8.6 Hz), 7.18 (d, 1H, J=8.8 Hz), 7.14(d, 1H, J=2.4 Hz), 7.10 (d, 2H, J=8.8 Hz), 6.79 (dd, 1H, J=8.8 Hz, 2.2Hz), 6.73 (s, 4H), 5.13 (s, 2H), 5.11 (s, 4H), 3.93 (t, 2H, J=5.9 Hz),2.62-2.53 (m, 4H), 2.40-2.33 (m, 4H), 1.49-1.42 (m, 4H), 1.37-1.30 (m,2H), 1.10 (t, 3H, J=7.2 Hz); MS eI m/z 650 (M+H+).

EXAMPLE NO. 1372-(4-Hydroxy-phenyl)-3-ethyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol(HCl)

Mp=160-164° C.; ¹H NMR (DMSO) 9.78 (br s, 1H), 9.69 (s, 1H), 8.69 (s,1H), 7.14 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=8.6 Hz), 6.87-6.78 (m, 7H),6.56 (dd, 1H, J=8.8 Hz, 2.4 Hz), 5.08 (s, 2H), 4.25 (t, 2H, J=4.4 Hz),3.45-3.38 (m, 5H), 3.00-2.86 (m, 2H), 2.57-2.50 (m, 2H), 1.83-1.59 (m,5H), 1.41-1.28 (m, 1H), 1.10 (t, 2H, J=7.5 Hz); IR (KBr) 3400 br, 3200br, 2920, 1610 cm⁻¹; MS eI m/z 470 (M+); CHN calcd forC₃₀H₃₄N₂O₃+HCl+1.5H₂O.

EXAMPLE NO. 155 5-Benzyloxy-3-cyano-2-(4-benzyloxy-phenyl)-1H-indole

In a reaction flask 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1H-indole No. 141(5.90 g, 14.6 mmol) was mixed with CH₂Cl₂ (90 mL) was cooled down to 0°C. (the starting material did not completely dissolve in CH₂Cl₂). Whilestirring vigorously, a solution of chlorosulfonyl isocyanate (2.26 g,16.0 mmol) in CH₂Cl₂ (25 mL) was added dropwise over a period of 45 min.The reaction was run at 0° C. for 2 hrs while detected by TLC for theformation of the insoluble N-chlorosulfonylamide intermediate. Afterthis period, Et₃N (1.47 g, 14.6 mL) in CH₂Cl₂ (25 mL) was added dropwiseover 45 min at 0° C. The insoluble residue became soluble in thereaction solvent as the Et₃N addition was approaching completion. Thereaction was let go for the additional 1 hr at 0° C. and 2 hrs at rt.The progress of the reaction could be observed by the insoluble solidformation of the product as the reaction time went on. The solvent wasstripped down and the solid residue purified by trituration withmethanol to yield (4.0 g, 63.8%). Mp=238-242° C.; ¹H NMR (DMSO) 12.31(s, 1H), 7.88 (d, 2H, J=8.8 Hz), 7.48 (d, 4H, J=7.25 Hz), 7.55-7.30 (m,7H), 7.23 (d, 2H, J=8.8 Hz), 7.14 (d, 1H, J=2.4 Hz), 6.97 (dd, 1H, J=2.2Hz, 8.8 Hz), 5.20 (s, 2H), 5.17 (s, 2H); MS eI m/z 430 (M+).

EXAMPLE NO. 156 4-(2-Chloroethoxy)benzylbromide

To 4-(2-Chloroethoxy)benzylalcohol CAS No. [111728-87-1] (6.4 g, 34.31mmol) in dioxane (100 mL) at 0° C. was added slowly thionylbromide (7.13g, 34.31 mmol). The reaction was run at 0° C. after 5 min. The reactionmixture was diluted with ether (200 mL) and washed with H₂O (1×30 mL)then NaHCO₃ (2×25 mL), and brine (30 mL). The organic extract was driedover MgSO₄ and concentrated. The crude product was purified by silicagel chromatography (15% EtOAc/Hex) to yield 5.0 g (58%) of the desiredproduct. Mp=64-66° C.; ¹H NMR (DMSO) 7.37 (d, 2H, J=8.8 Hz), 6.93 (d,2H, J=8.8 Hz), 4.68 (s, 2H), 4.24 (t, 2H, J=5.05 Hz), 3.93 (t, 2H,J=5.27 Hz); MS eI m/z 248 (M+).

EXAMPLE NO. 157Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(2-chloro-ethoxy)-benzyl]-3-cyano-1H-indole

In a reaction flask the 3-cyano indole starting material No. 155 (2.86g, 6.64 mmol) was dissolved in DMF (25 mL) at 0° C. was added NaH (191.2mg, 8 mmol) slowly. The reaction was stirred at 0° C. for 20 min. In aseparate reaction flask containing 4-(2-Chloroethoxy)benzylbromide No.156 (1.81 g, 7.28 mmol) in DMF (15 mL) at 0° C., the above preparedindole anion solution taken up by syringe was added slowly. The reactionwas stirred at 0° C. for 20 min and promoted to rt for 1 h. The reactionwas quenched with a few drops of H₂O. The reaction mixture waspartitioned between EtOAc (2×100 mL) and H₂O (80 mL). The organicextract was washed with brine (80 mL), dried over MgSO₄, andconcentrated. The crude product was purified by trituration with etherto give the product as a white solid (2.80 g, 70.4%). Mp=160-162° C.; ¹HNMR (DMSO) 7.53-7.28 (m, 13H), 7.23 (m, 3H), 6.97 (dd, 1H, J=2.4 Hz, 9.0Hz), 6.86-6.78 (m, 4H), 5.37 (s, 2H), 5.18 (s, 4H), 4.15 (t, 2H, J=4.8Hz), 3.87 (t, 2H, J=5.3 Hz); MS eI m/z 598 (M+).

EXAMPLE NOS. 158 AND 159

Substitution of the chloro group with piperidine and hexamethyleneaminewas performed analogously to the procedure outlined in method 6 usingNo. 157 as a starting material, supra.

EXAMPLE NO. 1585-Benzyloxy-2-(4-benzyloxy-phenyl)-3-cyano-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

Mp=148-150° C.; ¹H NMR (DMSO) 7.54-7.30 (m, 13H), 7.25-7.18 (m, 3H),6.98 (dd, 1H, J=2.4 Hz, 9.0 Hz), 6.84-6.74 (m, 4H), 5.35 (s, 2H), 5.17(s, 4H), 3.94 (t, 2H, 5.9 Hz), 2.55 (t, 2H, 5.7 Hz), 2.35 (bs, 4H),1.50-1.40 (m, 4H), 1.38-1.25 (m, 2H); IR 3400, 2910, 2250, 1250 cm⁻¹; MSFAB 648 [M+H]+.

EXAMPLE NO. 1595-Benzyloxy-2-(4-benzyloxy-phenyl)-3-cyano-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole

¹H NMR (DMSO) 8.60 (br s, 1H), 7.60-7.28 (m, 12H), 7.25-7.16 (m, 3H),6.97 (dd, 1H, J=2.4 Hz, 9.0 Hz), 6.88-6.75 (m, 4H), 5.35 (s, 2H), 5.17(s, 4H), 3.92 (t, 2H, J=6.2 Hz), 3.08-3.00 (m, 2H), 2.77 (t, 2H, J=5.9Hz), 2.63 (t, 4H, J=4.8 Hz), 1.78-1.68 (m, 2H), 1.60-1.40 (m, 4H); MS eIm/z 661 (M+).

EXAMPLES NO. 138 AND NO. 139

Benzyl ethers were removed by hydrogen transfer using 1,4 cyclohexadieneand 10% Pd/C as described in method 7. Compounds were converted intotheir respective hydrochloride salts as described in method 8.

EXAMPLE NO. 1385-Hydroxy-2-(4-Hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole-3-carbonitrile(HCl)

Mp=173-175° C.; ¹H NMR (DMSO) 10.40 (s, 1H), 10.12 (s, 1H), 9.40 (s,1H), 7.38 (m, 2H), 7.30 (d, 1H, J=8.8 Hz), 7.02-6.90 (m, 3H), 6.88 (s,4H), 6.75 (dd, 1H, J=2.4 Hz, 9 Hz), 5.33 (s, 2H), 4.30 (t, 2H, J=4.8Hz), 3.51-3.38 (m, 4H), 2.92 (m, 2H), 1.85-1.73 (m, 4H), 1.68-1.59 (m,1H), 1.26-1.21 (m, 1H); IR 3400, 2200, 1250 cm⁻¹; MS eI m/z 467 (M+);CHN calcd for C₂₉H₂₉N₃O₃+1.0 HCl+1.0H₂O.

EXAMPLE NO. 1391-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-hydroxy-2-(4-hydroxy-phenyl)-1H-indole-3-cabonitrile(HCl)

Mp=160-163° C.; ¹H NMR (DMSO) 10.22 (s, 1H), 10.08 (s, 1H), 9.35 (s,1H), 7.40-7.37 (m, 2H), 7.30 (d, 1H, 8.8 Hz), 7.0-6.90 (m, 3H), 6.87 (s,4H), 6.74 (dd, 1H, J=2.41 Hz, 9 Hz), 5.33 (s, 2H), 4.27 (t, 2H, J=5.0Hz), 3.50-3.30 (m, 4H), 3.20 (m, 2H), 1.85-1.70 (m, 4H), 1.65-1.50 (m,4H); IR 3300, 2200, 1250 cm⁻¹; MS eI m/z 481 (M+); CHN calc forC₃₀H₃₁N₃O₃+1HCl+1H₂O.

Esters of Indole No.'s 97 and 98

TABLE 9

Example No. R Z No. 160 Et

No. 161 t-Bu

No. 162 t-Bu

Method 9 EXAMPLE NO. 162 Di-pivalate Ester of2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol

Example No. 97 free base was used as the starting material for thissynthesis. No. 97 (1.0 g, 2.5 mmol) in 20 mL CH₂Cl₂ was treated withdiisopropylethylamine (0.7 g, 6.3 mmol) and cataltic DMAP. The reactionwas cooled to 0° C. and treated with pivaloyl chloride (0.7 mL, 5.6mmol) and allowed to come to rt and stirred overnight. The reaction wasworked up by diluting with CH₂Cl₂ and washing with water and brine.After drying over MgSO₄ the solution was concentrated andchromatographed on silica gel (MeOH/CH₂Cl₂, 1:19) to yield the desiredmaterial as an orange foam (1.08 g). This material was then taken up in15 mL ethyl acetate and treated with 2.5 mL of a 1M HCl/Et₂O solution.Hexane was added until the solution turned cloudy. The productprecipitated out as the HCl salt. This material was recrystallized fromethyl acetate/hexane to yield 0.42 g of pure No. 162: Mp=182-185° C.;CHN calcd for C₃₉H₄₈N₂O₅+HCl+0.25H₂O.

EXAMPLE NO. 160 Di-propionate of1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol(HCl)

Compound was prepared analogously to example No. 162 except the startingmaterial used was example No. 98 and the acylating agent used waspropionyl chloride: Mp=170.5-172° C.; CHN calcd forC₃₆H₄₂N₂O₅+HCl+0.75H₂O; MS FAB 605 (M+Na)+.

EXAMPLE NO. 161 Di-pivalate of1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol(HCl)

Compound was prepared analogously to example No. 162 except the startingmaterial used was example No. 98: Mp=143-151° C.; CHN calcd forC₄₀H₅₀N₂O₅+HCl+0.75H₂O.

Experimental for Example No. 166

EXAMPLE NO. 1662-(4-Hydroxy-phenyl)-3-methyl-1-{4-[3-(piperidin-1-yl)-propoxy]-benzyl}-1H-indol-5-ol

The title compound was prepared according to Scheme 16 and the stepsprovided below:

Method 11 EXAMPLE NO. 163a 4-(3-chloropropoxy)-benzyl Alcohol

A solution of 4-hydroxy benzyl alcohol CAS No. [623-05-2] (10 g, 80.5mmol) in ethanol (70 mL) was treated with 1,3 bromochloro propane (16.0g, 100 mmol) and potassium hydroxide (5.0 g, 89 mmol) was refluxed for 2hours. The solution was cooled and filtered and then the filtrateconcentrated. The concentrate was taken up in ether and washed withwater, brine and dried over magnesium sulfate. The material waschromatographed on silica gel using ethyl acetate/hexanes (3:7) to yield11.6 g of the product as a white solid: Mp=65° C.; ¹H NMR (DMSO) 7.21(d, 2H, J=8.8 Hz), 6.88 (d, 2H, J=8.8 Hz), 5.03 (t, 1H, J=5.7 Hz), 4.40(d, 2H, J=5.5 Hz), 4.05 (t, 2H, J=6.1 Hz), 3.77 (t, 2H, J=6.4 Hz); MS eIm/z 200.

Method 12 EXAMPLE NO. 163b 4-(3-chloropropoxy)-benzyl bromide

A solution consisting of 4-(3-chloropropoxy)-benzyl alcohol No. 162(10.6 g, 52.8 mmol) in dioxane (0.125 l) was cooled to 0° C. and treatedwith a dropwise addition of thionyl bromide (12.0 g, 58.0 mmol). After10 minutes the reaction was complete. The dioxane was diluted with ethylether and washed with water, brine, and then dried over MgSO₄. Thematerial was concentrated down to yield 15 g of an oil: ¹H NMR (DMSO)7.36 (d, 2H, J=8.8 Hz), 6.92 (d, 2H, J=8.6 Hz), 4.68 (s, 2H), 4.08 (t,2H, J=5.9 Hz), 3.77 (t, 2H, J=6.4 Hz); MS (FAB) 266 (M+H⁺).

Method 13 EXAMPLE NO. 1645-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-chloro-propoxy)-benzyl]-3-methyl-1H-indole

A solution consisting of5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole No. 7 (6.5 g, 15.5mmol) in DMF (60 mL) was cooled to 0° C. and treated with addition ofsodium hydride (0.68 g, 17.0 mmol) and stirred for 20 minutes. Asolution of 4-(3-chloropropoxy)-benzyl bromide No. 163 in DMF (10 mL)was then added slowly. The reaction was allowed to come to rt andstirred for 2 hours. The reaction was poured into water and extractedwith ethyl acetate. The ethyl acetate was washed with water, brine anddried over magnesium sulfate and concentrated. The concentrate wastreated with methanol and 5 g of the desired product precipitated as awhite solid with a melting point of 130-132° C.

Method 14 EXAMPLE NO. 1655-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-3-methyl-1H-indole

A solution of5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-chloro-propoxy)-benzyl]-3-methyl-1H-indoleNo. 164 (3 g, 5.1 mmol), potassium iodide (2.5 g, 15.3 mmol) andpiperidine (3.0 mL, 30.6 mmol) were heated in DMF (30 mL) at 100° C. for18 hours. The reaction was worked up by pouring into water andextracting with ethyl acetate. The organic layer was washed with water,brine and dried over magnesium sulfate. The solution was concentrated toan oil and the product precipitated out by adding methanol. The productwas obtained as a white solid: Mp=104-106° C.; ¹H NMR (DMSO) 7.47 (d,4H, J=7.5 Hz), 7.38 (q, 4H, J=7.9 Hz), 7.36-7.30 (m, 1H), 7.28 (d, 2H,J=8.3 Hz), 7.19 (d, 1H, J=8.8 Hz), 7.12-7.10 (m, 4H), 6.80 (dd, 1H,J=8.8, 2.0 Hz), 6.72 (s, 4H), 5.14 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H),3.86 (t, 2H, J=6.4 Hz), 2.35-2.20 (m, 6H), 2.14 (s, 3H), 1.78-1.75 (m,2H), 1.47-1.42 (m,4H), 1.40-1.31 (m, 2H); MS eI m/z 650.

Method 15 EXAMPLE NO. 1662-(4-Hydroxy-phenyl)-3-methyl-1-{4-[3-(piperidin-1-yl)-propoxy]-benzyl}-1H-indol-5-ol

A solution of5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-3-methyl-1H-indoleNo. 165 (2.35 g) in tetrahydrofuran (25 mL) and ethanol (25 mL) wasadded to 2.3 g of 10% palladium on carbon. Cyclohexadiene (10 mL) wasadded and the reaction allowed to stir at room temperature for 18 hours.The catalyst was filtered through celite and the reaction mixture wasconcentrated and chromatographed on silica gel usingdichloromethane/methanol (4:1) to elute the product (0.8 g) as a whitefoam: Mp=125-130° C.; ¹H NMR 9.68 (s, 1H), 8.70 (s, 1H), 7.15 (d, 2H,J=8.6 Hz), 7.05 (d, 1H, J=8.8 Hz), 6.85 (d, 2H, J=8.6 Hz), 6.80 (d, 1H,J=2.4 Hz), 6.74 (d, 4H, J=2.6 Hz), 6.57 (dd, 1H, J=8.6, 2.2 Hz), 5.09(s, 2H), 3.88 (t, 2H, J=6.4 Hz), 3.60-3.15 (m, 2H), 2.62-2.38 (m, 4H),2.09 (s, 3H), 1.92-1.78 (m, 2H), 1.55-1.43 (m, 4H), 1.42-1.30 (m, 2H);IR (KBr) 3400 (br), 2900, 1620, 1515 cm−1; MS eI m/z 470.

Synthesis of No. 167 and No. 168

TABLE 10

Example No. Z No. 167

No. 168

Synthesis of Example No. 1672-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-methyl-1H-indol-5-olEXAMPLE NO. 169 (4-Formyl-2-methoxy-phenoxy)-acetic acid ethyl ester

A flask containing vanillin (20 g, 0.13 mol), ethyl bromoacetate (28.4g, 0.17 mol) and potassium carbonate (32.7 g, 0.24 mol) and acetone 200mL were heated to reflux for 3 hours. The reaction was allowed to cometo rt. The acetone was stripped off and the residue partitioned betweenwater and ethyl acetate. The ethyl acetate was washed with brine anddried over magnesium sulfate. The organic layer was concentrated and thesolid triturated with hexanes to yield 28.4 grams of example No. 169.

Mp=56-59° C.; ¹H NMR (DMSO) 9.83 (s, 1H), 7.50 (dd, 1H, J=2.0 Hz, 8.3Hz), 7.42 (d, 1H, J=1.7 Hz), 7.07 (d, 1H, J=8.4 Hz), 4.91 (s, 2H), 4.16(q, 2H, J=7.2 Hz), 3.84 (s, 3H), 1.20 (t, 3H, J=7.1 Hz); MS eI m/z 238(M+); CHN calcd for C₁₂H₁₄O₅.

EXAMPLE NO. 170 (4-Chloromethyl-2-methoxy-phenoxy)-acetic acid ethylester

A solution of example No. 169 (28.8 g, 0.119 mol) in 600 mL of EtOH/THF(1:1) was treated with sodium borohydride (2.25 g, 0.06 mol) at 0° C.and stirred for 45 minutes. The solvents were evaporated and thereaction mixture diluted with ethyl acetate and washed with 1N HClsolution. The product thus obtained (14.2 g, 0.059 mol) as an oil wasdissolved in 140 mL of THF and cooled to 0° C. This solution was thentreated with dropwise addition of thionyl chloride (7.38 g, 0.062 mol)at 0° C. After 1 hour the reaction was poured into 400 mL of water andextracted with ether. The ether layer was washed with a sodiumbicarbonate solution and dried over magnesium sulfate. This wasconcentrated and chromatographed by silica gel chromatography usingethyl acetate/hexanes (1:9). The product was obtained as 10.5 g of awhite solid. Mp=64-66° C.; ¹H NMR (DMSO) 7.06 (d, 1H, J=2.0 Hz), 6.91(dd, 1H, J=2.0 Hz, 2.2 Hz), 6.83 (d, 1H, J=2.1 Hz), 4.75 (s, 2H), 4.70(s, 2H), 4.13 (q, 2H, J=7.2 Hz), 3.77 (s, 3H), 1.19 (t, 3H, J=7.1 Hz);MS eI m/z 258 (M+); CHN calcd for C₁₂H₁₅ClO₄.

EXAMPLE NO. 171{2-Methoxy-4-[5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-aceticacid ethyl ester

Alkylation of the indole No. 7 was performed as described previously inMethod No. 3 using example No. 170 as the electrophile.

Mp=120-123° C.; ¹H NMR (DMSO) 7.48-7.20 (m, 13H), 7.18-7.10 (m, 3H),6.80 (dd, 1H, J=2.5 Hz, 8.8 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.52 (d, 1H,J=2.0 Hz), 6.24 (dd, 1H, J=1.9 Hz, 8.1 Hz), 5.13 (s, 4H), 5.10 (s, 2H),4.61 (s, 2H), 4.10 (q, 2H, J=7.0 Hz), 3.58 (s, 3H), 2.15 (s, 3H), 1.15(t, 3H, J=7.0 Hz); MS eI m/z 641 (M+).

EXAMPLE NO. 1722-{2-Methoxy-4-[5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol

Reduction of the ester No. 171 was performed as described previously inMethod 4.

Mp=86-90° C.; ¹H NMR (DMSO) 7.48-7.20 (m, 13H), 7.18-7.10 (m, 3H), 6.80(dd, 1H, J=2.5 Hz, 8.8 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.52 (d, 1H, J=2.0Hz), 6.24 (dd, 1H, J=1.9 Hz, 8.1 Hz), 5.13 (s, 4H), 5.10 (s, 2H), 4.76(t, 1H, J=5.5 Hz), 3.83 (t, 2H, J=5.1 Hz), 3.63 (q, 2H, J=5.3 Hz), 3.56(s, 3H), 2.15 (s, 3H); MS eI m/z 599 (M+).

EXAMPLE NO. 1735-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[3-methoxy-4-(2-bromo-ethoxy)-benzyl]-3-methyl-1H-indole

Conversion of the alcohol of example No. 172 to the bromide wasperformed analogously to that described in Method 5.

Mp=150-152° C.; ¹H NMR (DMSO) 7.48-7.20 (m, 13H), 7.18-7.10 (m, 3H),6.80 (dd, 1H, J=2.5 Hz, 8.8 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.52 (d, 1H,J=2.0 Hz), 6.24 (dd, 1H, J=1.9 Hz, 8.1 Hz), 5.13 (s, 4H), 5.10 (s, 2H),4.15 (t, 2H, J=5.3 Hz), 3.70 (t, 2H, J=5.7 Hz), 3.58 (s, 3H), 2.15 (s,3H); MS eI m/z 661 (M+).

EXAMPLE NO. 1745-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[3-Methoxy-4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole

Substitution of the bromide with piperidine was performed as describedpreviously in Method 6.

¹H NMR (DMSO) 7.48-7.20 (m, 13H), 7.18-7.10 (m, 3H), 6.80 (dd, 1H, J=2.5Hz, 8.8 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.52 (d, 1H, J=2.0 Hz), 6.24 (dd,1H, J=1.9 Hz, 8.1 Hz), 5.13 (s, 4H), 5.10 (s, 2H), 3.90 (t, 2H, J=5.7Hz), 3.55 (s, 3H), 2.62-2.50 (bs, 2H), 2.45-2.30 (bs, 4H), 2.15 (s, 3H),1.50-1.40 (m, 4H), 1.40-1.35 (m, 2H); MS FAB m/z 667 (M+H+).

EXAMPLE NO. 1755-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[2-Methoxy-4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole

Reaction performed exactly as for No. 174 except hexamethyleneamine wasused to displace the bromide in place of piperidine.

Foam; ¹H NMR (DMSO) 7.48-7.20 (m, 13H), 7.18-7.10 (m, 3H), 6.80 (dd, 1H,J=2.5 Hz, 8.8 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.52 (d, 1H, J=2.0 Hz), 6.24(dd, 1H, J=1.9 Hz, 8.1 Hz), 5.13 (s, 4H), 5.10 (s, 2H), 3.90 (t, 2H,J=5.7 Hz), 3.55 (s, 3H), 2.85-2.70 (bs, 2H), 2.70-2.55 (s, 4H), 2.10 (s,3H), 1.60-1.15 (m, 8H); MS FAB m/z 681 (M+H+)

EXAMPLE NO. 1672-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-methyl-1H-indol-5-ol

Compound No. 173 was hydrogenated by transfer hydrogenation as describedpreviously in Method 7. Compound was isolated as the hydrochloride saltby dissolving in ether and treating with 1.2 equivalents of 1N ether/HClsolution (this is a variation of method 8).

Mp=123-127° C.; ¹H NMR (DMSO) 10.20 (bs, 1H), 9.72 (s, 1H), 8.71 (s,1H), 7.17 (d, 2H, J=8.6 Hz), 7.11 (d, 1H, J=8.8 Hz), 6.87 (d, 2H, J=8.6Hz), 6.79 (m, 2H), 6.57 (dd, 1H, J=2.4 Hz, 8.8 Hz), 6.55 (d, 1H, J=1.7Hz), 6.33 (dd, 1H, J=1.7 Hz, 8.1 Hz), 5.11 (s, 2H), 4.23 (t, 2H, J=4.8Hz), 3.60 (s, 3H), 3.45 (m, 2H), 3.35 (m, 2H), 2.95 (m, 2H), 2.10 (s,3H), 1.70 (m, 5H), 1.35 (m, 1H); IR 3500, 1500, 1275 cm⁻¹; MS (+) FABm/z 487 (M+H)⁺; CHN calcd for C₃₀H₃₄N₂O₄+1HCl+1.0H₂O.

EXAMPLE NO. 1682-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-azepan-1-yl-ethoxy)-benzyl]-3-methyl-1H-indol-5-ol

Prepared in the same way as that described for example No. 167.

Mp=142-146° C.; ¹H NMR (DMSO) 10.36 (s, 1H), 9.72 (s, 1H), 8.71 (s, 1H),7.18 (d, 2H, J=8.3 Hz), 7.11 (d, 1H, J=8.6 Hz), 6.87 (d, 2H, J=8.3 Hz),6.82 (d, 1H, J=8.1 Hz), 6.79 (d, 1H, J=2.2 Hz), 6.57 (dd, 1H, J=2.2 Hz,8.6 Hz), 6.55 (d, 1H, J=1.8 Hz), 6.33 (dd, 1H, J=1.5 Hz, 8.1 Hz), 5.11(s, 2H), 4.24 (t, 2H, J=4.6 Hz), 3.60 (s, 3H), 3.40 (m, 4H), 3.20 (m,2H), 2.10 (s, 3H), 1.75 (m, 4H), 1.55 (m, 4H); IR (KBr) 3300, 1500,1270, 1200 cm⁻¹; MS (+) FAB m/z 501 (M+H)⁺; CHN calcd forC₃₁H₃₆N₂O₄+1.0HCl+0.12CH₃OH.

Biological Data

Method 16

In Vitro Estrogen Receptor Binding Assay

Receptor Preparation

CHO cells overexpressing the estrogen receptor were grown in 150 mm²dishes in DMEM+10% dextran coated charcoal, stripped fetal bovine serum.The plates were washed twice with PBS and once with 10 mM Tris-HCl, pH7.4, 1 mM EDTA. Cells were harvested by scraping the surface and thenthe cell suspension was placed on ice. Cells were disrupted with ahand-held motorized tissue grinder using two, 10-second bursts. Thecrude preparation was centrifuged at 12,000 g for 20 minutes followed bya 60 minute spin at 100,000 g to produce a ribosome free cytosol. Thecytosol was then frozen and stored at −80° C. Protein concentration ofthe cytosol was estimated using the BCA assay with reference standardprotein.

Binding Assay Conditions

The competition assay was performed in a 96-well plate (polystyrene*)which binds <2.0% of the total input [³H]-17β-estradiol and each datapoint was gathered in triplicate. 100 uG/100 uL of the receptorpreparation was aliquoted per well. A saturating dose of 2.5 nM[³H]17β-estradiol+competitor (or buffer) in a 50 uL volume was added inthe preliminary competition when 100× and 500× competitor wereevaluated, only 0.8 nM [³H] 17β-estradiol was used. The plate wasincubated at room temperature for 2.5 h. At the end of this incubationperiod 150 uL of ice-cold dextran coated charcoal (5% activated charcoalcoated with 0.05% 69K dextran) was added to each well and the plate wasimmediately centrifuged at 99 g for 5 minutes at 4° C. 200 uL of thesupernatant solution was then removed for scintillation counting.Samples were counted to 2% or 10 minutes, whichever occurs first.Because polystyrene absorbs a small amount of [³H]17β-estradiol, wellscontaining radioactivity and cytosol, but not processed with charcoalwere included to quantitate amounts of available isotope. Also, wellscontaining radioactivity but no cytosol were processed with charcoal toestimate unremovable DPM of [³H] 17β-estradiol. Corning No. 25880-96,96-well plates were used because they have proven to bind the leastamount of estradiol.

Analysis of Results

Counts per minute (CPM) of radioactivity were automatically converted todisintegrated per minute (DPM) by the Beckman LS 7500 ScintillationCounter using a set of quenched standards to generate a H No. for eachsample. To calculate the % of estradiol binding in the presence of 100or fold 500 fold competitor the following formula was applied:((DPM sample−DPM not removed by charcoal/(DPM estradiol−DPM not removedby charcoal))×100%=% of estradiol binding

For the generation of IC₅₀ curves, % binding is plotted vs compound.IC₅₀'s are generated for compounds that show >30% competition at 500×competitor concentration. For a description of these methods, see Hulme,E. C., ed. 1992. Receptor-Ligand Interactions: A Practical Approach. IRLPress, New York. (see especially chapter 8). TABLE 11 Estrogen ReceptorBinding

Receptor Example Binding No. X Q Z IC50's uM No. 85 H H

0.45 No. 86 H 4′-OH

0.12 No. 87 OH H

0.030 No. 88 OMe 4′-OH

0.35 No. 89 OH 4′-OMe

0.30 No. 90 OMe 4′-OMe

0.60 No. 91 OMe 4′-OMe

0.52 No. 92 OH 4′-OEt

0.062 No. 93 OH 4′-OEt

0.090 No. 94 F 4′-OH

0.20 No. 97 OH 4′-OH

0.060 No. 98 OH 4′-OH

0.050 No. 99 OH 4′-OH

0.03 No. 100 OH 4′-OH

0.06 No. 101 OH 4′-OH

0.04 No. 102 OH 4′-OH

0.08 No. 103 OH 4′-OH

0.2 No. 104 OH 4′-OH

0.1 No. 105 OH 4′-OH

0.028 No. 106 OH 4′-OH

0.1 No. 107 OH 4′-OH

0.06 No. 108 OH 4′-OH

0.02 No. 109 OH 4′-OH

0.17 No. 110 OH 4′-OH

0.037 No. 111 OH 4′-OH

0.15 No. 112 OH 4′-OH

0.07 No. 113 OH 4′-OH

0.047 No. 114 OH 4′-OH

0.001 No. 115 OH 4′-OH

0.15 No. 116 OH 4′-Fl

0.04 No. 117 OH 4′-Fl

0.10 No. 118 OH 3′-OMe, 4′-OH

N/A No. 119 OH 3′,4′- OCH₂O—

0.070 No. 120 OH 4′-O-iPr

0.10 No. 121 OH 4′-O-iPr

0.080 No. 122 OH 4′-O-Cp

0.080 No. 123 OH 4′-CF₃

0.17 No. 124 OH 4′-CH₃

0.11 No. 125 OH 4′-Cl

0.11 No. 126 OH 2′,4′,- Dimethoxy

N/A No. 127 OH 3′-OH

0.019 No. 128 OH 3′-OH

0.009 No. 129 OH 4′-OH, 3′-Fl

0.0055 No. 130 OH 4′-OH, 3′-Fl

0.013 No. 131 OH 3′-OMe

0.12 No. 132 OH 4′-OCF₃

0.05

TABLE 12 Estrogen Receptor Binding

Receptor Example Binding No. X Q Z IC50's uM No. 133 Cl H

0.004 No. 134 Cl H

0.024 No. 135 Cl H

0.029 No. 136 Cl CH₃

0.013 No. 137 Et H

0.15 No. 138 CN H

0.011 No. 139 CN H

0.023

TABLE 13 Estrogen Receptor Binding

Receptor Binding Example No. R Z IC50's uM No. 160 Et

N/A No. 161 t-Bu

N/A No. 162 t-Bu

Does not Bind

TABLE 14 Estrogen Receptor Binding

Receptor Example Binding No. X Q Z IC50's uM No. 166 OH 4′-OH

0.099

TABLE 15 Estrogen Receptor Binding

Receptor Binding Example No. Z IC50's uM No. 167

0.08 No. 168

0.057

Method 17

Ishikawa Cell Alkaline Phosphatase Assay

Cell Maintenance and Treatment:

Ishikawa cells were maintained in DMEM/F12 (50%:50%) containing phenolred+10% fetal bovine serum and the medium was supplemented with 2 mMGlutamax, 1% Pen/Strap and 1 mM sodium pyruvate. Five days prior to thebeginning of each experiment (treatment of cells) the medium was changedto phenol red-free DMEM/F12+10% dextran coated charcoal stripped serum.On the day before treatment, cells were harvested using 0.5%trypsin/EDTA and plated at a density of 5×10⁴ cells/well in 96-welltissue culture plates. Test compounds were dosed at 10⁻⁶, 10⁻⁷ and 10⁻⁸M in addition to 10⁻⁶ M (compound)+10⁻⁹ M 17β-estradiol to evaluate theability of the compounds to function as antiestrogens. Cells weretreated for 48 h prior to assay. Each 96-well plate contained a17β-estradiol control. Sample population for at each dose was n=8.

Alkaline Phosphatase Assay:

At the end of 48 h the media is aspirated and cells are washed threetimes with phosphate buffered saline (PBS). 50 μL of lysis buffer (0.1 MTris-HCl, pH 9.8, 0.2% Triton X-100) is added to each well. Plates areplaced at −80° C. for a minimum of 15 minutes. Plates are thawed at 37°C. followed by the addition of 150 μL of 0.1 M Tris-HCl, pH 9.8,containing 4 mM para-nitrophenylphosphate (pNPP) to each well (finalconcentration, 3 mM pNPP).

Absorbance and slope calculations were made using the KineticCalcApplication program (Bio-Tek Instruments, Inc., Winooski, Vt.). Resultsare expressed as the mean+/−S.D. of the rate of enzyme reaction (slope)averaged over the linear portion of the kinetic reaction curve (opticaldensity readings every 5 minutes for 30 minutes absorbance reading).Results for compounds are summarized as percent of response related to 1nM 17β-estradiol.

Various compounds were assayed for estrogenic activity by the alkalinephosphatase method and corresponding ED50 values (95% C.I.) werecalculated. The four listed in the following were used as referencestandards: 17β-estradiol 0.03 nM 17α-estradiol 1.42 nM estriol 0.13 nMestrone 0.36 nM

A description of these methods is described by Holinka, C. F., Hata, H.,Kuramoto, H. and Gurpide, E. (1986) Effects of steroid hormones andantisteroids on alkaline phosphatase activity in human endometrialcancer cells (Ishikawa Line). Cancer Research, 46:2771-2774, and byLittlefield, B. A., Gurpide, E., Markiewicz, L., McKinley, B. andHochberg, R. B. (1990) A simple and sensitive microtiter plate estrogenbioassay based on stimulation alkaline phosphatase in Ishikawa cells;Estrogen action of D5 adrenal steroids. Endocrinology, 6:2757-2762.

Ishikawa Alkaline Phosphatase Assay Compound % Activation 17β-estradiol100% activity tamoxifen  0% activity (45% with 1 nM 17β-estradiol)raloxifene  5% activity (5% with 1 nM 17β-estradiol) Example No. 98  1%activity (1% with 1 nM 17β-estradiol)

Method No. 18

2×VIT ERE Infection Assay

Cell Maintenance and Treatment

Chinese Hamster Ovary cells (CHO) which had been stably transfected withthe human estrogen receptor were maintained in DMEM+10% fetal bovineserum (FBS). 48 h prior to treatment the growth medium was replaced withDMEM lacking phenol red+10% dextran coated charcoal stripped FBS(treatment medium). Cells were plated at a density of 5000 cells/well in96-well plates containing 200 μL of medium/well.

Calcium Phoshate Transfection

Reporter DNA (Promega plasmid pGL2 containing two tandem copies of thevitellogenin ERE in front of the minimal thymidine kinase promoterdriving the luciferase gene) was combined with the B-galactosidaseexpression plasmid pCH110 (Pharmacia) and carrier DNA (pTZ18U) in thefollowing ratio:

-   -   10 uG of reporter DNA    -   5 uG of pCH110DNA    -   5 uG of pTZ18U    -   20 uG of DNA/1 mL of transfection solution

The DNA (20 uG) was dissolved in 500 uL of 250 mM sterile CaCl₂ andadded dropwise to 500 uL of 2×HeBS (0.28 M NaCl, 50 mM HEPES, 1.5 mMNa₂HPO₄, pH 7.05) and incubated at room temperature for 20 minutes. 20uL of this mixture was added to each well of cells and remained on thecells for 16 h. At the end of this incubation the precipitate wasremoved, the cells were washed with media, fresh treatment media wasreplaced and the cells were treated with either vehicle, 1 nM17β-estradiol, 1 uM compound or 1 uM compound+1 nM 17β-estradiol (testsfor estrogen antagonism). Each treatment condition was performed on 8wells (n=8) which were incubated for 24 h prior to the luciferase assay.

Luciferase Assay

After 24 h exposure to compounds, the media was removed and each wellwashed with 2× with 125 uL of PBS lacking Mg⁺⁺ and Ca⁺⁺. After removingthe PBS, 25 uL of Promega lysis buffer was added to each well andallowed to stand at room temperature for 15 min, followed by 15 min at−80° C. and 15 min at 37° C. 20 uL of lysate was transferred to anopaque 96 well plate for luciferase activity evaluation and theremaining lysate (5 uL) was used for the B-galactosidase activityevaluation (normalize transfection). The luciferan substrate (Promega)was added in 100 uL aliquots to each well automatically by theluminometer and the light produced (relative light units) was read 10seconds after addition.

Infection Luciferase Assay (Standards) Compound % Activation17β-estradiol 100% activity estriol  38% activity tamoxifen  0% activity(10% with 1 nM 17β-estradiol) raloxifene  0% activity (0% with 1 nM17β-estradiol)B-Galactosidase Assay

To the remaining 5 uL of lysate 45 uL of PBS was added. Then 50 uL ofPromega B-galactosidase 2× assay buffer was added, mixed well andincubated at 37° C. for 1 hour. A plate containing a standard curve (0.1to 1.5 milliunits in triplicate) was set up for each experimental run.The plates were analyzed on a Molecular Devices spectrophotometric platereader at 410 nm. The optical densities for the unknown were convertedto milliunits of activity by mathematical extrapolation from thestandard curve.

Analysis of Results

The luciferase data was generated as relative light units (RLUs)accumulated during a 10 second measurement and automatically transferredto a JMP (SAS Inc) file where background RLUs were subtracted. TheB-galactosidase values were automatically imported into the file andthese values were divided into the RLUs to normalize the data. The meanand standard deviations were determined from a n=8 for each treatment.Compounds activity was compared to 17β-estradiol for each plate.Percentage of activity as compared to 17β-estradiol was calculated usingthe formula %=((Estradiol−control)/(compound value))×100. Thesetechniques are described by Tzukerman, M. T., Esty, A., Santiso-Mere,D., Danielian, P., Parker, M. G., Stein, R. B., Pike, J. W. andMcDonnel, D. P. (1994). Human estrogen receptor transactivationalcapacity was determined by both cellular and promoter context andmediated by two functionally distinct intramolecular regions (seeMolecular Endocrinology, 8:21-30). TABLE 16 Infection LuciferaseActivity Example No. 1 uM 1 uM + 17β estradiol No. 85 −2 43 No. 86 −5 2No. 87 0 0 No. 88 4 44 No. 89 16 18 No. 90 3 58 No. 91 −3 56 No. 92 −4−2 No. 93 −3 −2 No. 94 −5 15 No. 95 −4 −4 No. 96 12 8 No. 97 −4 −5 No.98 5 5 No. 99 5 6 No. 100 9 10 No. 101 14 9 No. 102 9 10 No. 103 13 10No. 104 7 7 No. 105 5 5 No. 106 10 81 No. 107 −1 54 No. 108 11 10 No.109 6 5 No. 110 8 10 No. 111 25 23 No. 112 10 10 No. 113 14 16 No. 114 1−1 No. 115 11 10 No. 116 −1 1 No. 117 0 1 No. 118 N/A N/A No. 119 −1 −1No. 120 −1 1 No. 121 0 1 No. 122 1 5 No. 123 −1 1 No. 124 −2 −2 No. 125−3 −2 No. 126 −1 0 No. 127 −3 −4 No. 132 −5 −2 No. 133 7 9 No. 134 9 5No. 135 7 3 No. 136 16 10 No. 137 6 8 No. 138 −2 −1 No. 139 −12 −13 No.160 N/A N/A No. 161 N/A N/A No. 162 −14 −13 No. 166 25 23 No. 167 4 10No. 168 3 7

Method No. 19

Rat Uterotrophic/Antiuterotrophic Bioassay

The estrogenic and antiestrogenic properties of the compounds weredetermined in an immature rat uterotrophic assay (4 day) that (asdescribed previously by L. J. Black and R. L. Goode, Life Sciences, 26,1453 (1980)). Immature Sprague-Dawley rats (female, 18 days old) weretested in groups of six. The animals were treated by daily ip injectionwith 10 uG compound, 100 uG compound, (100 uG compound+1 uG17β-estradiol) to check antiestrogenicity, and 1 uG 17β-estradiol, with50% DMSO/50% saline as the injection vehicle. On day 4 the animals weresacrificed by CO₂ asphyxiation and their uteri were removed and strippedof excess lipid, any fluid removed and the wet weight determined. Asmall section of one horn was submitted for histology and the remainderused to isolate total RNA in order to evaluate complement component 3gene expression. TABLE 17 3 Day Rat Immature Uterine Assay Uterine wtUterine wt mg Uterine wt mg 100 uG cmpd + 1 uG mg Uterine wt 100 uG 17β-1 uG 17β- mg Example No. cmpd estradiol estradiol Vehicle Tamoxifen 71.4mg N/A 98.2 mg 42.7 mg No. 85 41.1 mg 92.4 mg 94.4 mg 26.6 mg No. 9428.1 mg 93.7 mg 88.5 mg 22.3 mg No. 97 27.4 mg 24.3 mg 63.2 mg 30.7 mgNo. 98 29.4 mg 27.9 mg 94.1 mg 35.9 mg No. 100 59.9 mg 68.7 mg 91.9 mg23.4 mg No. 101 65.1 mg 71.0 mg 113.7 mg  27.7 mg No. 122 46.7 mg 38.7mg 103.4 mg  30.3 mg No. 123 39.2 mg 61.4 mg 94.4 mg 26.1 mg No. 13828.4 mg 37.9 mg 93.9 mg 24.6 mg No. 139 30.4 mg 45.0 mg 82.1 mg 20.5 mgNo. 168 43.2 mg 81.7 mg 98.9 mg 25.5 mg

Method No. 20

6-Week Ovariectomized Rat Model

Female Sprague Dawley CD rats, ovx or sham ovx, were obtained 1 dayafter surgery from Taconic Farm (weight range 240-275 g). They werehoused 3 or 4 rats/cage in a room on a 14/10 (light/dark) schedule andprovided with food (Purina 500 rat chow) and water ad libitum. Treatmentfor all studies began 1 day after the animals arrival and dosed 5 or 7days per week as indicated for 6 weeks. A group of age matched shamoperated rats not receiving any treatment served as an intact, estrogenreplete control group for each study. All treatments were prepared in 1%tween 80 in normal saline at defined concentrations so that thetreatment volume was 0.1 mL/100 g body weight. 17-beta estradiol wasdissolved in corn oil (20 uG/mL) and delivered subcutaneously, 0.1mL/rat. All dosages were adjusted at three week intervals according togroup mean body weight measurements.

Five weeks after the initiation of treatment and one week prior to thetermination of the study, each rat was evaluated for bone mineraldensity (BMD). The BMD's of the proximal tibiae (PT) and fourth lumbarvertabrae (L4) were measured in anesthetized rats using a dual energyX-ray absorptiometer (Eclipse XR-26, Norland Corp. Ft. Atkins, Wis.).The dual energy X-ray absorptiometer (DXA) measurements for each ratwere performed as follows: Fifteen minutes prior to DXA measurements,the rat was anesthetized with an intraperitoneal injection of 100 mg/kgketamine (Bristol Laboratories, Syracuse, N.Y.) and 0.75 mg/kgacepromazine (Aveco, Ft. Dodge, Iowa). The rat was placed on an acrylictable under the DXA scanner perpendicular to its path; the limbs wereextended and secured with paper tape to the surface of the table. Apreliminary scan was performed at a scan speed of 50 mm/second with ascan resolution of 1.5 mm×1.5 mm to determine the region of interest inPT and L4. Small subject software was employed at a scan speed of 10mm/second with resolution of 0.5 mm×0.5 mm for final BMD measurements.The software allows the operator to define a 1.5 cm wide area to coverthe total length of L4. The BMDs for respective sites were computed bythe software as a function of the attenuation of the dual beam (46.8 KeVand 80 KeV) X-ray generated by the source underneath the subject and thedetector travelling along the defined area above the subject. The datafor BMD values (expressed in g/cm2) and individual scans were stored forstatistical analysis.

One week after BMD evaluation the rats were sacrificed by carbon dioxidesuffocation and blood collected for cholesterol determination. The uteriwere removed and the weights taken. Total cholesterol is determinedusing a Boehringer-Mannheim Hitachi 911 clinical analyzer using theCholesterol/HP kit. Statitstics were compared using one-way analysis ofvariance with Dunnet's test. TABLE 18 6-Week Ovariectomized Rat Study OfExample No. 98 BMD (mg/cm²)^(a,b) Δ Body Uterine Proximal Weight WeightCholesterol Treatment Tibia L₄ (g)^(a,c) (mg)^(a,c) (mg/dl)^(a,c)Study^(d) Sham (Intact) 0.211** ± 0.003  0.183* ± 0.003  43.0* ± 6.0 426.4** ± 25.0   71.6** ± 5.0   Vehicle (Ovx) 0.189 ± 0.004 0.169 ±0.004 62.7 ± 8.2  118.2 ± 7.8  87.2 ± 3.0  Example No. 98 0.210** ±0.003  0.173 ± 0.003 46.8 ± 6.6  149.3 ± 4.4  59.0** ± 2.2   0.3 mg/kg,p.o. Raloxifene 0.207** ± 0.006  0.170 ± 0.003 25.3** ± 5.4   191.6** ±9.3   55.0** ± 2.4     3 mg/kg, p.o. 17β-Estradiol 0.224** ± 0.004 0.169 ± 0.004 33.1** ± 4.9   426.0** ± 18.4   95.5 ± 3.9    2 μg/rat,s.c.^(a)Mean ± SEM^(b)Following 5 weeks of treatment^(c)Following 6 weeks of treatment^(d)Daily treatment ×7 days/week ×6 weeks*p < 0.05 vs corresponding Vehicle value**p < 0.01 vs corresponding Vehicle value

1. A method of treating uterine leiomyoma in a mammal in need thereof,which comprises administering to said mammal an effective amount of acompound of formula I or II, having the structures

wherein: R₁ is selected from H, OH or the C₁-C₁₂ esters (straight chainor branched) or C₁-C₁₂ (straight chain or branched or cyclic) alkylethers thereof, or halogens; or C₁-C₄ halogenated ethers includingtrifluoromethyl ether and trichloromethyl ether; R₂, R₃, R₄, R₅, and R₆are independently selected from H, OH or the C₁-C₁₂ esters (straightchain or branched) or C₁-C₁₂ alkyl ethers (straight chain or branched orcyclic) thereof, halogens, or C₁-C₄ halogenated ethers includingtrifluoromethyl ether and trichloromethyl ether, cyano, C₁-C₆ alkyl(straight chain or branched), or trifluoromethyl, with the proviso that,when R₁ is H, R₂ is not OH; X is selected from H, C₁-C₆ alkyl, cyano,nitro, trifluoromethyl, halogen; n is 2 or 3; Y is selected from: a) themoiety:

wherein R₇ and R₈ are independently selected from the group of H, C₁-C₆alkyl, or phenyl optionally substituted by CN, C₁-C₆ alkyl (straightchain or branched), C₁-C₆ alkoxy (straight chain or branched), halogen,—OH, —CF₃, or —OCF₃; b) a five-membered saturated, unsaturated orpartially unsaturated heterocycle containing up to two heteroatomsselected from the group consisting of —O—, —NH—, —N(C₁C₄ alkyl)-, —N═,and —S(O)_(m)—, wherein m is an integer of from 0-2, optionallysubstituted with 1-3 substituents independently selected from the groupconsisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl,C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—,—CONHR₁—, —NH₂—, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R₁—,—NHCOR₁—, —NO₂, and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl;c) a six-membered saturated, unsaturated or partially unsaturatedheterocycle containing up to two heteroatoms selected from the groupconsisting of —O—, —NH—, —N(C₁C₄ alkyl)-, —N═, and —S(O)_(m)—, wherein mis an integer of from 0-2, optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; d) a seven-membered saturated,unsaturated or partially unsaturated heterocycle containing up to twoheteroatoms selected from the group consisting of —O—, —NH—, —N(C₁C₄alkyl)-, —N═, and —S(O)_(m)—, wherein m is an integer of from 0-2,optionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; or e) a bicyclic heterocyclecontaining from 6-12 carbon atoms either bridged or fused and containingup to two heteroatoms selected from the group consisting of —O—, —NH—,—N(C₁C₄ alkyl)-, and —S(O)_(m)—, wherein m is an integer of from 0-2,optionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄) alkyl; and the pharmaceutically acceptablesalts thereof.
 2. The method according to claim 1 wherein: R₁ isselected from H, OH or the C₁-C₄ esters or alkyl ethers thereof,halogen; R₂, R₃, R₄, R₅, and R₆ are independently selected from H, OH orthe C₁-C₄ esters or alkyl ethers thereof, halogen, cyano, C₁-C₆ alkyl,or trifluoromethyl, with the proviso that, when R₁ is H, R₂ is not OH; Xis selected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl, halogen;Y is the moiety

R₇ and R₈ are selected independently from H, C₁-C₆ alkyl, or combined by—(CH₂)p—, wherein p is an integer of from 2 to 6, so as to form a ring,the ring being optionally substituted by up to three substituentsselected from the group of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN,—CONH(C₁-C₄), —NH₂, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino,—NHSO₂(C₁-C₄), —NHCO(C₁-C₄), and —NO₂; or a pharmaceutically acceptablesalt thereof.
 3. The method according to claim 1 wherein: R₁ is OH; R₂,R₃, R₄, R₅, and R₆ are independently selected from H, OH or the C₁-C₄esters or alkyl ethers thereof, halogen, cyano, C₁-C₆ alkyl, ortrifluoromethyl, with the proviso that, when R₁ is H, R₂ is not OH; X isselected from the group of Cl, NO₂, CN, CF₃, or CH₃; Y is the moiety

R₇ and R₈ are concatenated together as —(CH₂)_(r)—, wherein r is aninteger of from 4 to 6, to form a ring optionally substituted by up tothree subsituents selected from the group of hydrogen, hydroxyl, halo,C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄), —NH₂, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄), —NHCO(C₁-C₄), and —NO₂; or apharmaceutically acceptable salt thereof.
 4. A method of treatinguterine leiomyoma in a mammal in need thereof, which comprisesadministering to said mammal an effective amount of a compound offormula I or II, having the structures

wherein: R₁ is selected from H, OH or the C₁-C₄ esters or alkyl ethersthereof, halogen; R₂, R₃, R₄, R₅, and R₆ are independently selected fromH, OH or the C₁-C₄ esters or alkyl ethers thereof, halogen, cyano, C₁-C₆alkyl, or trifluoromethyl, with the proviso that, when R₁ is H, R₂ isnot OH; X is selected from H, C₁-C₆ alkyl, cyano, nitro,trifluoromethyl, halogen; n is 2 or 3; and Y is the moiety

R₇ and R₈ are selected independently from H, C₁-C₆ alkyl, or combined by—(CH₂)p—, wherein p is an integer of from 2 to 6, so as to form a ring,the ring being optionally substituted by up to three substituentsselected from the group of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN,—CONH(C₁-C₄), —NH₂, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino,—NHSO₂(C₁-C₄), —NHCO(C₁-C₄), and —NO₂; or a pharmaceutically acceptablesalt thereof.
 5. The method according to claim 4 wherein: R₁ is OH; R₂,R₃, R₄, R₅, and R₆ are independently selected from H, OH or the C₁-C₄esters or alkyl ethers thereof, halogen, cyano, C₁-C₆ alkyl, ortrifluoromethyl, with the proviso that, when R₁ is H, R₂ is not OH; X isselected from the group of Cl, NO₂, CN, CF₃, or CH₃; Y is the moiety

R₇ and R₈ are concatenated together as —(CH₂)_(r)—, wherein r is aninteger of from 4 to 6, to form a ring optionally substituted by up tothree subsituents selected from the group of hydrogen, hydroxyl, halo,C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄), —NH₂, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄), —NHCO(C₁-C₄), and —NO₂; or apharmaceutically acceptable salt thereof.
 6. The method according toclaim 4, wherein the compound is1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-olor a pharmaceutically acceptable salt thereof.
 7. The method accordingto claim 4, wherein the compound is2-(4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-olor a pharmaceutically acceptable salt thereof.